Thieno [2, 3-b] pyridine derivatives as viral replication inhibitors

ABSTRACT

The present invention relates to a series of compounds having antiviral activity, more specifically HIV (Human Immunodeficiency Virus) replication inhibiting properties. The invention also relates to methods for the preparation of such compounds, as well as to novel intermediates useful in one or more steps of such syntheses. The invention also relates to pharmaceutical compositions comprising an effective amount of such compounds as active ingredients. This invention further relates to the use of such compounds as medicines or in the manufacture of a medicament useful for the treatment of animals suffering from viral infections, in particular HIV infection. This invention further relates to methods for the treatment of viral infections in animals by the administration of a therapeutic amount of such compounds, optionally combined with one or more other drugs having anti-viral activity.

FIELD OF THE INVENTION

The present invention relates to a series of novel compounds havingantiviral activity, more specifically HIV (Human Immunodeficiency Virus)replication inhibiting properties. The invention also relates to methodsfor the preparation of such compounds, as well as to novel intermediatesuseful in one or more steps of such syntheses. The invention alsorelates to pharmaceutical compositions comprising an effective amount ofsuch compounds as active ingredients. This invention further relates tothe compounds for use as a medicine, to the use of such compounds asmedicines, or in the manufacture of a medicament useful for thetreatment of animals suffering from viral infections, in particular HIVinfection. This invention further relates to methods for the treatmentof viral infections in animals by the administration of atherapeutically effective amount of such compounds, optionally combinedwith one or more other drugs having anti-viral activity.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV) is theetiological agent of the complex disease that includes progressivedestruction of the immune system (acquired immune deficiency syndrome,hereinafter AIDS) and degeneration of the central and peripheral nervoussystem. There are two types of HIV, HIV-1 and HIV-2, the latterproducing a less severe disease than the former. Being a retrovirus, itsgenetic material is in the form of RNA (ribonucleic acid) consisting oftwo single RNA strands. Coexisting with RNA are reverse transcriptase(having polymerase and ribonuclease activity), integrase, a protease andother proteins.

It is known in the art that some antiviral compounds which act asinhibitors of HIV replication are effective agents in the treatment ofAIDS and similar diseases. Drugs that are known and approved for thetreatment of HIV-infected patients belong to one of the followingclasses:

-   -   nucleoside reverse transcriptase (RT) inhibitors such as, but        not limited to, azidothymidine (AZT), and lamivudine (3TC),    -   nucleotide reverse transcriptase inhibitors such as, but not        limited to, tenofovir (R-PMPA),    -   non-nucleoside reverse transcriptase inhibitors such as, but not        limited to, nevirapine, efavirenz,    -   protease inhibitors such as, but not limited to, nelfinavir,        saquinavir, ritonavir and amprenavir,    -   fusion inhihitors such as enfuvirtide, and    -   integrase inhibitors such as raltegravir or elvitegravir.

Replication of the human immunodeficiency virus type 1 (hereinafterreferred as HIV-1) can be drastically reduced in infected patients bycombining potent antiviral drugs targeted at multiple viral targets, asreviewed by Vandamme at al. in Antiviral Chem. Chemother. (1998)9:187-203.

Multiple-drug combination regimes can reduce viral load below thedetection limit of the most sensitive tests. Nevertheless low levelongoing replication has been shown to occur, possibly in sanctuarysites, leading to the emergence of drug-resistant strains, according toPerelson et al. in Nature (1997) 387:123-124. Furthermore theselectivity of many antiviral agents is rather low, possibly making themresponsible for side-effects and toxicity. Moreover, HIV can developresistance to most, if not all, currently approved antiviral drugs,according to Schmit et al. in J. Infect. Dis. (1996) 174:962-968. It iswell documented that the ability of HIV to rapidly evolve drugresistance, together with toxicity problems resulting from known drugs,requires the development of additional classes of antiviral drugs.

As a summary, there is still a stringent need in the art for potentinhibitors of HIV. Therefore a goal of the present invention is tosatisfy this urgent need by identifying efficient pharmaceuticallyactive ingredients that are active against HIV, less toxic, more stable(i.e. chemically stable, metabolically stable), effective againstviruses resistant to currently available drugs and/or which are moreresistant to virus mutations than existing antiviral drugs and that canbe useful, either alone or in combination with other active ingredients,for the treatment of retroviral infections, in particular lentiviralinfections, and more particularly HIV infections, in mammals and morespecifically in humans. It is also known to the skilled in the art thatthe physicochemical properties of known drugs as well as their ADME-Tox(administration, distribution, metabolism, excretion) properties maylimit or prohibit their use in the treatment of diseases. Therefore, aproblem of existing drugs that can be overcome with the compounds of theinvention can be selected from a poor or inadequate physicochemical orADME-Tox properties such as solubility, LogP, CYP inhibition, hepaticstability, plasmatic stability, among others have been taken intoaccount in the design and the synthesis of the compounds of the presentinvention. Furthermore, another goal of the present invention is tocomplement existing antiviral drugs in such a way that the resultingdrug combination has improved activity or improved resistance to virusmutation than each of the individual compounds.

The prior art describes a small number of thieno[2,3-b]pyridines with astructure similar to the thieno[2,3-b]pyridines of the invention, but nomedical use is known for these compounds.

SUMMARY OF THE INVENTION

The present invention is based on the unexpected finding that at leastone of the above-mentioned problems can be solved by a novel class ofthieno[2,3-b]pyridines and derivatives thereof.

The present invention provides new anti-viral agents, especiallyanti-retroviral agents, and more particularly anti-HIV compounds. Thesecompounds are thieno[2,3-b]pyridines, or analogues or derivativesthereof, which have been shown to possess anti-viral activity, morespecifically against HIV. The present invention demonstrates that thesecompounds efficiently inhibit the replication of HIV. Therefore, thesethieno[2,3-b]pyridines constitute a useful class of new potentanti-viral compounds that can be used in the treatment and/or preventionof viral infections in animals, mammals and humans, more specificallyfor the treatment and/or prevention of HIV in humans.

The present invention furthermore relates to the compounds for use as amedicine, to the use of such compounds as medicines, more specificallyas anti-viral agents, and to their use for the manufacture ofmedicaments for treating and/or preventing viral infections, inparticular retroviral infections such as, but not limited to, HIV inhumans. The invention also relates to methods for the preparation of allsuch compounds and to pharmaceutical compositions comprising them in ananti-viral effective amount.

The present invention also relates to a method of treatment orprevention of viral infections, in particular retroviral infections suchas, but not limited to HIV in humans by the administration of one ormore such compounds, optionally in combination with one or more otheranti-viral agents, to a patient in need thereof.

One aspect of the present invention is the provision of novelthieno[2,3-b]pyridine compounds, said compounds having a structureaccording to the formula (A):

wherein,

R¹ is independently selected from alkyl; alkenyl; alkynyl; cycloalkyl;cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; orheterocycle-alkynyl;

-   -   wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms in the cycloalkyl, cycloalkenyl, cycloalkynyl,        alkyl, alkenyl or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,        heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,        heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

each of R^(2a) and R^(2b) is independently selected from hydrogen;cyano; alkyl; alkenyl; alkynyl; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl or whenR^(2a) and R^(2b) are taken together to form vinyl or vinylalkyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl,        heterocycle-alkynyl or vinylalkyl optionally includes one or        more heteroatoms, said heteroatoms in the alkyl, alkenyl or        alkynyl moiety being selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, heterocycle-alkynyl, vinyl or vinylalkyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, heterocycle-alkynyl, or vinylalkyl can be        taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂.

R³ is independently selected from —COOH; —CN; —CONH₂; —COOZ²; —C(O)NHCN;—C(O)NHOH; —S(O)₂OH; —S(O)₂NHZ⁴; —P(O)(OH)NH₂; —P(O)(O-alkyl)₂;—P(O)(OH)O-alkyl; —P(O)OH₂; —NHC(O)NHS(O)₂-aryl;—NHC(O)NHS(O)₂-heteroaryl; —C(O)NHS(O)₂-aryl; C(O)NHS(O)₂-heteroaryl;—S(O)₂NHS(O)₂-aryl; —S(O)₂NHS(O)₂-heteroaryl; or from the followingstructures:

or

R²² and R³ or R^(2b) and R³ can be taken together to form a 4, 5, 6 or 7membered lactone;

R⁴ is independently selected from hydrogen; halogen; cyano; hydroxyl;alkyl; alkenyl, alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or        heterocycle-alkynyl, optionally includes one or more heteroatoms        in the alkyl, alkenyl or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be unsubstituted        or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be taken        together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;

each R⁵ and R⁶ is independently selected from hydrogen; halogen; cyano;—S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl, alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or        heterocycle-alkynyl, optionally includes one or more heteroatoms        in the alkyl, alkenyl, or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl, can be        unsubstituted or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be taken        together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; or        R⁵ and R⁶ are taken together to form a 4, 5, 6, 7 or 8-membered        unsaturated ring together with the carbon atoms to which they        are attached;    -   wherein said 4, 5, 6, 7 or 8-membered unsaturated ring        optionally includes one or more heteroatoms, said heteroatoms        being selected from the atoms O, S and N;    -   and wherein said 4, 5, 6, 7 or 8-membered unsaturated ring can        be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said 4, 5, 6, 7 or 8-membered unsaturated ring can        be taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;

each Z¹ is independently selected from the group consisting of hydrogen;halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl;nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³ cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with one or more Z¹¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; or

two Z¹ on the same carbon atom can be taken together to form a 5, 6 or7-membered spiro-cycloalkyl, spiro-cycloalkenyl, spiro-cycloalkynyl or asaturated or unsaturated spiro-heterocycle together with the (4, 5, 6, 7or 8-membered) ring they are attached to; or

two Z¹ on adjacent atoms can be taken together to form a 5, 6 or7-membered cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocyclefused to the (4, 5, 6, 7 or 8-membered) ring they are attached to;

each Z¹¹ is independently selected from the group consisting ofhydrogen; halogen; —OZ¹²; —SZ¹²; —S(O)Z¹³; —S(O)₂Z¹³; —SO₂NZ¹⁴Z¹⁵;trifluoromethyl; nitro; —NZ¹⁴Z¹⁵; —NZ¹²S(O)₂Z¹³; cyano; —COOZ¹²;—C(O)NZ¹⁴Z¹⁵; —C(O)Z¹³; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl;

each Z² and Z¹² is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl optionallyinclude one or more heteroatoms, said heteroatom selected from O, S andN; and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted orsubstituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or NH₂; andwherein optionally two or more hydrogens on a carbon atom or heteroatomof said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be taken together to form a C═O, C═S, N═O, N═S,S═O or S(O)₂;

each Z³ and Z¹³ is independently selected from hydroxyl; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, cyano, nitro, —COOH or NH₂; andwherein optionally two or more hydrogens on a carbon atom or heteroatomof said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be taken together to form a C═O, C═S, N═O, N═S,S═O or S(O)₂;

each Z⁴, Z⁵, Z¹⁴ and Z¹⁵ is independently selected from hydrogen; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl optionally includes one ormore heteroatoms, said heteroatom selected from O, S and N; and whereinsaid alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be unsubstituted or substituted with alkyl,alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl,—OCF₃, cyano, nitro, —COOH or NH₂; and wherein optionally two or morehydrogens on a carbon atom or heteroatom of said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can betaken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; and whereinZ⁴ and Z⁵, and Z¹⁴ and Z¹⁵ respectively can be taken together in orderto form a (5-, 6-, or 7-membered) heterocycle which can be unsubstitutedor substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or —NH₂;

and isomers (in particular stereo-isomers or tautomers), solvates,hydrates, salts (in particular pharmaceutically acceptable salts) orprodrugs thereof.

In a particular embodiment, R⁵ and R⁶ are taken together to form a 5, 6,or 7-membered unsaturated ring together with the carbon atoms to whichthey are attached.

In a particular embodiment of this aspect, the compounds of theinvention are not selected from:

-   -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-(2-methoxy-5-methylphenyl)-4-phenyl- or        also        [2-(2-methoxy-5-methylphenyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        4-(2-furanyl)-5,6,7,8-tetrahydro-2,7-dimethyl- or also        [2,7-dimethyl-4-(2-furanyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-methyl-4-(2-thienyl)- or also        [4-(2-thienyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2,7-dimethyl-4-phenyl- or also        [2,7-dimethyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2,7-dimethyl-4-(3-methylphenyl)- or also        [2,7-dimethyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-methyl-4-(3-methylphenyl)- or also        [2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        4-(4-chlorophenyl)-5,6,7,8-tetrahydro-2-methyl- or also        [4-(4-chlorophenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        4-(4-chlorophenyl)-6,7-dihydro-2-methyl- or also        [4-(4-chlorophenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-2-methyl- or also        [4-(p-anisyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-phenyl-2-(2-thienyl)-, ethyl ester or also        Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        6,7-dihydro-4-(4-methylphenyl)-2-(2-thienyl)-, ethyl ester or        also        Ethyl[2-(2-thienyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-methyl-4-(4-methylphenyl)- or also        [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-phenyl-2-(2-thienyl)- or also        [4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        2-(4-ethoxyphenyl)-6,7-dihydro-4-(4-methylphenyl)- or also        [2-(4-ethoxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-(4-iodophenyl)-4-phenyl- or also        [2-(4-iodophenyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        6,7-dihydro-4-(4-methylphenyl)-2-(4-propoxyphenyl)- or also        [2-(4-propoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        2-(3,4-dipropoxyphenyl)-6,7-dihydro-4-(4-methylphenyl)- or also        [2-(3,4-dipropoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-(4-methylphenyl)-2-(2-thienyl)- or also        [2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        6,7-dihydro-4-(4-methylphenyl)-2-[4-(pentyloxy)phenyl]- or also        [2-(4-pentyloxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        6,7-dihydro-4-(4-methylphenyl)-2-(2-thienyl)-, ethyl ester or        also        Ethyl[4-(p-tolyl)-2-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-phenyl-2-(2-thienyl)-, ethyl ester or also        Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        4-(3-fluorophenyl)-5,6,7,8-tetrahydro-2-methyl- or also        [4-(3-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   5H-Cyclopenta[4,5]thieno[2,3-b]pyridine-3-acetic acid,        6,7-dihydro-2-methyl-4-(4-methylphenyl)- or also        [2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-methyl-4-phenyl- or also        [2-methyl-4-phenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-4-(4-methylphenyl)-2-(2-thienyl)- or also        [2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid;    -   [1]Benzothieno[2,3-b]pyridine-3-acetic acid,        5,6,7,8-tetrahydro-2-methyl-4-(4-methylphenyl)- or also        [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic        acid.

In a particular embodiment, R¹ is selected from substituted orunsubstituted aryl, heteroaryl, C₁-C₆ alkyl, —O-aryl, —S-aryl, —NH-aryl,—O-heterocycle, —S-heterocycle, and —NH-heterocycle, (preferably fromaryl or heteroaryl), and yet in a more particular embodiment is selectedfrom phenyl, —O-phenyl, —S-phenyl, —NH-phenyl, pyridinyl, furanyl,thiophenyl, indolyl, benzofuranyl, t-butyl, and benzo[d][1,3]dioxolyl(preferably benzo[d][1,3]dioxol-5-yl), preferably R¹ is selected fromphenyl, wherein said aryl, heteroaryl, C₁-C₆ alkyl, —O-aryl, —S-aryl,—NH-aryl, —O-heterocycle, —S-heterocycle, and —NH-heterocycle(preferably from aryl or heteroaryl), or more particularly phenyl,—O-phenyl, —S-phenyl, —NH-phenyl, pyridinyl, furanyl, thiophenyl,indolyl, benzofuranyl, t-butyl, and benzo[d][1,3]dioxolyl (preferablybenzo[d][1,3]dioxol-5-yl), preferably phenyl, can be unsubstituted orsubstituted, in a particular embodiment substituted with Z¹. Preferably,R¹ is selected from phenyl, tolyl, chlorophenyl, dichlorophenyl,fluorophenyl, trifluoromethylphenyl, ethylphenyl, methoxyphenyl,dimethoxyphenyl, trifluoromethoxyphenyl, pyridinyl, furanyl, thiophenyl,indolyl, benzofuranyl, t-butyl, benzo[d]dioxolyl (preferablybenzo[d][1,3]dioxol-5-yl), 2,3-dihydropyrano[4,3,2-de]quinolinyl,chromanyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl,1,2,3,4-tetrahydroquinolinyl, and 2,3-dihydrobenzofuranyl.

In another particular embodiment, R¹ is substituted phenyl, in aparticular embodiment substituted with one or more Z¹. Preferably R¹ isphenyl substituted with one or more groups selected from methyl, ethyl,chloro, fluoro, trifluoromethyl, hydroxyl, and methoxy. More preferably,R¹ is p-tolyl, unsubstituted or substituted with one or more Z¹. Moreparticularly, R¹ is o-hydroxy-p-tolyl.

In another particular embodiment, one of R^(2a) and R^(2b) is nothydrogen. Preferably, one of R^(2a) and R^(2b) is hydrogen and the otherone is selected from the group consisting of C₁-C₆ alkyl andC₁-C₆-alkoxy, more preferably selected from the group consisting ofC₁-C₄ alkyl and C₁-C₄-alkoxy, preferably n-propyl and butoxy, or one ofR^(2a) and R^(2b) is hydrogen and the other one is taken together withR³ to form a gamma-lactone radical, preferably a dihydrofuran-2(3H)-oneradical.

In yet another particular embodiment, R³ is selected from —COOH,COOalkyl (preferably —COOMe or —COOEt, more preferably —COOMe), —CN,—C(O)NH₂, —C(O)NH(CN), —P(O)OH₂;

preferably R³ is —COOH or —COOalkyl (preferably —COOMe or —COOEt, morepreferably —COOMe), more preferably R³ is —COOH.

In yet another particular embodiment, R⁴ is selected from hydrogen,hydroxyl, alkyl or aryl, wherein said alkyl and aryl can beunsubstituted or substituted, in a particular embodiment substitutedwith Z¹. Preferably, R⁴ is selected from preferably hydrogen, alkyl oraryl, wherein said alkyl and aryl can be unsubstituted or substituted,in a particular embodiment substituted with Z¹. More preferably, R⁴ isselected from C₁-C₄ alkyl, even more preferably R⁴ is methyl.

In still another embodiment, R⁵ and R⁶ are taken together to form a 5, 6or 7-membered unsaturated ring together with the carbon atoms to whichthey are attached;

-   -   wherein said 5, 6 or 7-membered unsaturated ring optionally        includes one or more heteroatoms, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said 5, 6 or 7-membered unsaturated ring can be        unsubstituted or substituted with one or more Z¹ as defined        herein;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said 5, 6 or 7-membered unsaturated ring can be        taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂,        preferably with the proviso that the C═O is not adjacent to a N        atom in a 6-membered ring, more particularly two or more        hydrogen atoms on a carbon atom or heteroatom of said 5, 6 or        7-membered unsaturated ring can be taken together to form a C═S,        N═O, N═S, S═O or S(O)₂.

In other words, in this particular embodiment R⁵ and R⁶ are takentogether to form a 5, 6 or 7-membered cycloalkenyl or aryl moiety or any5, 6 or 7-membered mono-unsaturated, multi-unsaturated or aromatic O, Sand/or N containing heterocycle, wherein said 5, 6 or 7-memberedcycloalkenyl or aryl moiety or any 5, 6 or 7-membered mono-unsaturated,multi-unsaturated or aromatic O, S and/or N containing heterocycle canbe unsubstituted or substituted with one or more Z¹ as defined herein,and wherein two or more hydrogen atoms on a carbon atom or heteroatom ofsaid 5, 6 or 7-membered cycloalkenyl or aryl moiety or any 5, 6 or7-membered mono-unsaturated, multi-unsaturated or aromatic O, S and/or Ncontaining heterocycle can be taken together to form a C═O, C═S, N═O,N═S, S═O or S(O)₂, preferably with the proviso that the C═O is notadjacent to a N atom in a 6-membered ring, more particularly two or morehydrogen atoms on a carbon atom or heteroatom of said 5, 6 or 7-memberedunsaturated ring can be taken together to form a C═S, N═O, N═S, S═O orS(O)₂. In yet another particular embodiment, each Z¹ is independentlyselected from the group consisting of hydrogen; halogen; —OZ²; —SZ²;—S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl; nitro; —NZ⁴Z⁵;—NZ²S(O)₂Z³ cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl;aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen,        —SH, trifluoromethyl, —OalkylO-alkyl, —OCF₃, cyano, nitro, —COOH        or NH₂;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; or

two Z¹ on the same carbon atom can be taken together to form a 5, 6 or7-membered spiro-cycloalkyl, spiro-cycloalkenyl, spiro-cycloalkynyl, ora saturated or unsaturated spiro-heterocycle together with the 5, 6 or7-membered unsaturated ring they are attached to; or

two Z¹ on adjacent atoms can be taken together to form a 5, 6 or7-membered cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocyclefused to the 5, 6 or 7-membered unsaturated ring they are attached to.

Preferably each Z¹ is independently selected from the group consistingof hydrogen; halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵;trifluoromethyl; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³ cyano; —COOZ²; —C(O)NZ⁴Z⁵;—C(O)Z³; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkyl;arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen,        —SH, trifluoromethyl, —OalkylO-alkyl, —OCF₃, cyano, nitro, —COOH        or NH₂;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;

In one embodiment, the invention relates to compounds of formula A,wherein

R¹ is independently selected from cycloalkyl; cycloalkenyl;cycloalkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms in the cycloalkyl, cycloalkenyl, cycloalkynyl,        alkyl, alkenyl or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,        heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,        heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂;

each of R^(2a) and R^(2b) is independently selected from hydrogen;cyano; alkyl; alkenyl; alkynyl; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl or whenR^(2a) and R^(2b) are taken together to form vinyl or vinylalkyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl,        heterocycle-alkynyl or vinylalkyl optionally includes one or        more heteroatoms, said heteroatoms in the alkyl, alkenyl or        alkynyl moiety being selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, heterocycle-alkynyl, vinyl or vinylalkyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, heterocycle-alkynyl, or vinylalkyl can be        taken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂.

R³ is independently selected from —COOH; —COOZ²; —C(O)NHCN; —S(O)₂OH;—S(O)₂NHZ⁴; —P(O)(OH)NH₂; —P(O)(OH)O-alkyl; —NHC(O)NHS(O)₂-aryl;—NHC(O)NHS(O)₂-heteroaryl; —C(O)NHS(O)₂-aryl; C(O)NHS(O)₂-heteroaryl;—S(O)₂NHS(O)₂-aryl; —S(O)₂NHS(O)₂-heteroaryl; or from the followingstructures:

R⁴ is independently selected from hydrogen; halogen; cyano; oxygen;alkyl; alkenyl, alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or        heterocycle-alkynyl, optionally includes one or more heteroatoms        in the alkyl, alkenyl or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be unsubstituted        or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be taken        together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;

each R⁵ and R⁶ is independently selected from hydrogen; halogen; cyano;—S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl, alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or        heterocycle-alkynyl, optionally includes one or more heteroatoms        in the alkyl, alkenyl, or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl, can be        unsubstituted or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be taken        together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; or        R⁵ and R⁶ are taken together to form a 5, 6 or 7-membered        unsaturated or saturated ring together with the carbon atoms to        which they are attached;    -   wherein said 5, 6 or 7-membered unsaturated or saturated ring        optionally includes one or more heteroatoms, said heteroatoms        being selected from the atoms O, S and N;    -   and wherein said 5, 6 or 7-membered unsaturated or saturated        ring can be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said 5, 6 or 7-membered unsaturated or saturated        ring can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

each Z¹ is independently selected from the group consisting of hydrogen;halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl;nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³ cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen,        —SH, trifluoromethyl, —Oalkyl, —OCF₃, cyano, nitro, —COOH or        NH₂;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂;

each Z² is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl optionallyinclude one or more heteroatoms, said heteroatom selected from O, S andN; and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted orsubstituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or NH₂; andwherein optionally two or more hydrogens on a carbon atom or heteroatomof said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be taken together to form a C═O, C═S, N═O, N═S,S═O or S(O)₂;

each Z³ is independently selected from hydroxyl; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —Oalkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally two or more hydrogens on a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be taken together to forma C═O, C═S, N═O, N═S, S═O or S(O)₂;

each Z⁴ and Z⁵ is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally two or more hydrogens on a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be taken together to forma C═O, C═S, N═O, N═S, S═O or S(O)₂; and wherein Z⁴ and Z⁵ can be takentogether in order to form a (5-, 6-, or 7-membered) heterocycle whichcan be unsubstituted or substituted with alkyl, alkenyl, alkynyl,hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro,—COOH or —NH₂;

and isomers (in particular stereo-isomers or tautomers), solvates,hydrates, salts (in particular pharmaceutically acceptable salts) orprodrugs thereof.

In another particular embodiment, the present invention provides forcompounds according to the formula A and embodiments thereof, wherein,

R¹ is independently selected from arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl,        optionally includes one or more heteroatoms in the alkyl,        alkenyl or alkynyl moiety, said heteroatoms being selected from        the atoms O, S and N;    -   and wherein said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂;

each R⁵ and R⁶ is independently selected from hydrogen; halogen; cyano;—S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl, alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,        arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, or        heterocycle-alkynyl, optionally includes one or more heteroatoms        in the alkyl, alkenyl, or alkynyl moiety, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl, can be        unsubstituted or substituted with one or more Z¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl, or heterocycle-alkynyl can be taken        together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; and wherein

all other substituents (such as each of R^(2a), R^(2b), R³, R⁴, etc.)are as provided for in the formula A or embodiments thereof.

It should be clear that all embodiments described herein, areembodiments which can be used for all formulae, claims and otherembodiments thereof described in the application.

In one particular embodiment, the compounds of the invention are notselected from compounds having a structure according to formula (D)

wherein each of R¹, R^(2a), R^(2b), R³, and R⁴ is as described hereinand the dotted line represents an optional double bond; and

each Z^(1′) is independently selected from the group consisting ofhydrogen; —OZ²; —SZ²; —S(O)₂Z³; —SO₂NZ⁴Z⁵; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkyl; arylalkynyl; heterocycle-alkyl; and

R′ is selected from hydrogen; —OZ²; —SZ²; —SO₂NZ⁴Z⁵; —NZ⁴Z⁵; —NZ²S(O)₂Z³cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkyl; heterocycle-alkyl.

In one embodiment, the compounds of the invention have a structureaccording to formula (A-1),

wherein each of R¹, R^(2a), R^(2b), R³, and R⁴ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond;

W, X, Y, and Z are independently selected from CR′, CR′R″, N, NR′″, Oand S depending on whether they are adjacent to a double or a singlebond, wherein R′, R″ and R′″ are independently selected from the groupconsisting of hydrogen; halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³;—SO₂NZ⁴Z⁵; trifluoromethyl; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³ cyano; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with Z¹¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂,    -   preferably with the proviso that the C═O is not adjacent to a N        atom in a 6-membered ring, more particularly two or more        hydrogens on a carbon atom or heteroatom of said alkyl, alkenyl,        alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═S, N═O, N═S, S═O or S(O)₂;

R′ or R″ on the same carbon atom can be taken together to form a 5, 6 or7-membered spiro-cycloalkyl, spiro-cycloalkenyl, spiro-cycloalkynyl or aa saturated or unsaturated spiro-heterocycle together with the 5, 6 or7-membered unsaturated ring they are attached to; or

an R′ and another R′, R″ or R′″ on adjacent atoms can be taken togetherto form a 5, 6 or 7-membered cycloalkyl, cycloalkenyl, cycloalkynyl,aryl or heterocycle fused to the 5, 6 or 7-membered unsaturated ringthey are attached to;

each Z¹¹ is independently selected from the group consisting ofhydrogen; halogen; —OZ¹²; —SZ¹²; —S(O)Z¹³; —S(O)₂Z¹³; —SO₂NZ¹⁴Z¹⁵;trifluoromethyl; nitro; —NZ¹⁴Z¹⁵; —NZ¹²S(O)₂Z¹³; cyano; —COOZ¹²;—C(O)NZ¹⁴Z¹⁵; —C(O)Z¹³; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl;

each Z² and Z¹² is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl optionallyinclude one or more heteroatoms, said heteroatom selected from O, S andN; and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted orsubstituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or NH₂; andwherein optionally two or more hydrogens on a carbon atom or heteroatomof said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be taken together to form a C═O, C═S, N═O, N═S,S═O or S(O)₂;

each Z³ and Z¹³ is independently selected from hydroxyl; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally two or more hydrogens on a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be taken together to forma C═O, C═S, N═O, N═S, S═O or S(O)₂;

each Z⁴, Z⁵, Z¹⁴ and Z¹⁵ is independently selected from hydrogen; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl optionally includes one ormore heteroatoms, said heteroatom selected from O, S and N; and whereinsaid alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be unsubstituted or substituted with alkyl,alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl,—OCF₃, cyano, nitro, —COOH or NH₂; and wherein optionally two or morehydrogens on a carbon atom or heteroatom of said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can betaken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂; and whereinZ⁴ and Z⁵, and Z¹⁴ and Z¹⁵ respectively can be taken together in orderto form a (5-, 6-, or 7-membered) heterocycle which can be unsubstitutedor substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or —NH₂; and

n is selected from 0; 1; or 2.

In one embodiment, the compounds of the invention have a structureaccording to formula (A-1′),

wherein each of R¹, R^(2a), R^(2b), R³, and R⁴ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond;

W, X, Y, and Z are independently selected from CR′, CR′R″, N, NR′″, Oand S depending on whether they are adjacent to a double or a singlebond, wherein R′, R″ and R′″ are independently selected from the groupconsisting of hydrogen; halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³;—SO₂NZ⁴Z⁵; trifluoromethyl; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³ cyano; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen,        —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or        NH₂;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂, preferably with the        proviso that the C═O is not adjacent to a N atom in a 6-membered        ring, more particularly two or more hydrogens on a carbon atom        or heteroatom of said alkyl, alkenyl, alkynyl, aryl,        heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═S, N═O, N═S, S═O or S(O)₂;

each Z² is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl optionallyinclude one or more heteroatoms, said heteroatom selected from O, S andN; and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted orsubstituted with alkyl, alkenyl, alkynyl, hydroxyl, halogen, —SH,trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH or NH₂; andwherein optionally two or more hydrogens on a carbon atom or heteroatomof said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be taken together to form a C═O, C═S, N═O, N═S,S═O or S(O)₂;

each Z³ is independently selected from hydroxyl; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally two or more hydrogens on a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be taken together to forma C═O, C═S, N═O, N═S, S═O or S(O)₂;

each Z⁴ and Z⁵ is independently selected from hydrogen; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally two or more hydrogens on a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be taken together to forma C═O, C═S, N═O, N═S, S═O or S(O)₂; and wherein Z⁴ and Z⁵ can be takentogether in order to form a (5-, 6-, or 7-membered) heterocycle whichcan be unsubstituted or substituted with alkyl, alkenyl, alkynyl,hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro,—COOH or —NH₂; and

n is selected from 0; 1; or 2.

In a particular embodiment, R′″ is selected from the group consisting ofhydrogen; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl; —NZ⁴Z⁵;—NZ²S(O)₂Z³; cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl;

-   -   and wherein said alkyl, alkenyl, alkynyl, arylalkyl,        arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl        or heterocycle-alkynyl, optionally includes one or more        heteroatoms, said heteroatoms being selected from the atoms O, S        and N;    -   and wherein said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be unsubstituted        or substituted with Z¹¹;    -   and wherein optionally two or more hydrogens on a carbon atom or        heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,        arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,        heterocycle-alkenyl or heterocycle-alkynyl can be taken together        to form a C═O, C═S, N═O, N═S, S═O or S(O)₂,    -   preferably with the proviso that the C═O is not adjacent to a N        atom in a 6-membered ring, more particularly two or more        hydrogens on a carbon atom or heteroatom of said alkyl, alkenyl,        alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═S, N═O, N═S, S═O or S(O)₂;        or R′″ can be together with R′, R″ on adjacent atoms to form a        5, 6 or 7-membered cycloalkyl, cycloalkenyl, cycloalkynyl, aryl        or heterocycle fused to the 5, 6 or 7-membered unsaturated ring        they are attached to.

In a particular embodiment, the compounds have a structure according toformula A-1 or A-1′, wherein:

W is selected from CH, CH₂ and NH;

X is selected from CR′, CR′R″, N, NR′″, O and S depending on whetherthey are adjacent to a double or a single bond, wherein R′, R″ and R′″are independently selected from the group consisting of hydrogen;C(O)Z³; and alkyl;

Y is selected from CR′, CR′R″, N, NR′, O and S depending on whether theyare adjacent to a double or a single bond, wherein R′, R″ and R′″ areindependently selected from the group consisting of hydrogen; C(O)Z³;and alkyl;

Z is selected from CH and CH₂.

In another embodiment, the compounds of the invention have a structureaccording to formula (A-2)

wherein each of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond;

X is defined as above in respect of formula A-1, preferably X isselected from the group consisting of CH₂, O, N, and NR′″, wherein R′″is as defined in respect of formula (A) or (A-1); and

m is selected from 0; 1; 2; 3; 4; 5; and 6.

Preferred compounds of formula (A-2) are those having a structureaccording to formula (A-3)

wherein each of R¹, R^(2a), R^(2b), R³, and R⁴ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond;

X is defined as above in respect of formula (A-1), preferably X isselected from the group consisting of CH₂, O, N, and NR′″, wherein R′″is as defined in respect of formula (A-1).

Preferred compounds of formulae (A-2) and (A-3) are those wherein eachof R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described herein, the dottedlines are absent, and X is selected from the group consisting of CH₂, Oand NR′″, wherein R′″ is selected from the group consisting of hydrogen,alkyl, and arylalkyl, preferably R′″ is selected from the groupconsisting of hydrogen, methyl, acetyl and benzyl.

In another embodiment, the compounds of the invention have a structureaccording to formula (B),

wherein each of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond;

n is selected from 0; 1; or 2; and

m is selected from 0; 1; 2; 3; 4; 5; 6; 7; 8; 9 or 10.

In a particular embodiment, m is selected from 0; 1; 2; 3; 4; 5 or 6.

In another embodiment, the compounds of the invention have a structureaccording to formula (B-1)

wherein each of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ as described hereinand

each dotted line represents an optional double bond whereby maximallyone dotted line can form a double bond; and

m is selected from 0; 1; 2; 3; 4; 5 or 6.

In yet another embodiment, the compounds of the invention have astructure according to formula (B-2)

wherein each of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond; and

m is selected from 0; 1; 2; 3; 4; 5; 6; 7; or 8.

In a particular embodiment, m is selected from 0; 1; 2; 3; and 4.

Preferred compounds of formula B-2 are those wherein each of R¹, R^(2a),R^(2b), R³, R⁴ and Z¹ is as described herein, m is 0, and the dottedlines are absent.

In still another embodiment, the compounds of the invention have astructure according to formula (B-3),

wherein each of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described hereinand

each dotted line represents an optional double bond whereby maximallytwo non-adjacent dotted lines can form a double bond; and

m is selected from 0; 1; 2; 3; 4; 5; 6; 7; 8; 9 or 10.

In a particular embodiment, m is selected from 0; 1; 2; 3; 4; 5 or 6.

Preferred compounds of formula B-3 are those wherein each of R¹, R^(2a),R^(2b), R³, R⁴ and Z¹ is as described herein, m is 0, and the dottedlines are absent.

Preferred compounds of formula B, B-1, B-2 and B-3 are those whereineach of R¹, R^(2a), R^(2b), R³, R⁴ and Z¹ is as described herein, m is0, and the dotted lines are absent. Other particular compounds offormula B, B-1, B-2 and B-3 are those wherein R¹ is selected from—O-aryl, —S-aryl, and —NH-aryl, preferably —O-phenyl, —S-phenyl,—NH-phenyl,

each of R^(2a), R^(2b), R³, R⁴ and Z¹ is as described herein and

each dotted line represents an optional double bond whereby maximallyone dotted line can form a double bond, preferably the dotted lines areabsent; and

m is selected from 0; 1; 2; 3; 4; 5 or 6, preferably m is 0.

Still other preferred compounds of formula B, B-1, B-2 and B-3 are thosewherein each of R¹, R^(2a), R^(2b), R⁴ and Z¹ is as described herein and

R³ is selected from —COON, COOalkyl (preferably —COOMe or —COOEt, morepreferably —COOMe), —CN, —C(O)NH₂, —C(O)NH(CN), —P(O)OH₂;

preferably from —CN, —C(O)NH₂, —C(O)NH(CN), —P(O)OH₂;

each dotted line represents an optional double bond whereby maximallyone dotted line can form a double bond, preferably the dotted lines areabsent; and

m is selected from 0; 1; 2; 3; 4; 5 or 6, preferably m is 0.

In another embodiment, the compounds of the invention have a structureaccording to formula (C) or (C′),

wherein each of R¹, R⁴, R⁵, R⁶, Z¹ and Z² are as described herein,including in the embodiments, and

R^(2a) is selected from cyano; alkyl; alkenyl; alkynyl; cycloalkyl;cycloalkenyl; cycloalkynyl; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        optionally includes one or more heteroatoms, said heteroatoms in        the cycloalkyl, cycloalkenyl, cycloalkynyl, alkyl, alkenyl or        alkynyl moiety being selected from the atoms O, S and N;    -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        vinyl or vinylalkyl, can be unsubstituted or substituted with        one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkynyl, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

In a more particular embodiment, the the compounds of the invention havea structure according to formula (C-1) or (C-1′),

wherein each of R¹, R⁴, W, X, Y, Z, the dotted lines, n, Z¹ and Z² areas described herein, including in the embodiments, and

R^(2a) is selected from cyano; alkyl; alkenyl; alkynyl; cycloalkyl;cycloalkenyl; cycloalkynyl; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        optionally includes one or more heteroatoms, said heteroatoms in        the cycloalkyl, cycloalkenyl, cycloalkynyl, alkyl, alkenyl or        alkynyl moiety being selected from the atoms O, S and N;    -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        vinyl or vinylalkyl, can be unsubstituted or substituted with        one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkynyl, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

In a yet more particular embodiment, the compounds of the invention havea structure according to formula (C-2) or (C-2′),

wherein each of R¹, R^(2a), R⁴, R⁵, R⁶, X, the dotted lines, m, Z¹ andZ² are as described herein for formula C-1 and C-1′.

In yet another embodiment, the compounds of the invention have astructure according to formula (C-3),

wherein each of R⁴, R⁵, R⁶ and Z¹ are as described herein, including inthe embodiments, and

R^(2a) is selected from cyano; alkyl; alkenyl; alkynyl; cycloalkyl;cycloalkenyl; cycloalkynyl; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl;

-   -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        optionally includes one or more heteroatoms, said heteroatoms in        the cycloalkyl, cycloalkenyl, cycloalkynyl, alkyl, alkenyl or        alkynyl moiety being selected from the atoms O, S and N;    -   wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloalkynyl, arylalkyl; arylalkenyl; arylalkynyl;        heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyl        vinyl or vinylalkyl, can be unsubstituted or substituted with        one or more Z¹;    -   and wherein optionally two or more hydrogen atoms on a carbon        atom or heteroatom of said alkyl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, cycloalkynyl, arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

p is selected from 0; 1; 2; 3; 4 or 5.

In a more particular embodiment, p is selected from 0; 1; 2 or 3.

Particular embodiments of this aspect are described in the claims andrelate to subtypes of the compounds of the invention. In particularembodiments, the terms alkyl, alkenyl or alkynyl can be restricted torefer to their cyclic or linear subgroups (such as the linear alkyl orcycloalkyl for alkyl).

In a particular embodiment, the compounds of the present invention areselected from the list of:

Methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;

Methyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate;

Methyl[7-methyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;

Methyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;

Methyl[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate;

Methyl[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Ethyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;

Ethyl2-[2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;

Ethyl2-[2-methyl-4-(p-tolyl)-spiro[[1,3]dioxolane-2,7]-5,6,7,8-tetrahydro-9-thia-1-aza-7-oxo-fluoren-3-yl]pentanoate;

Ethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl 2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl 2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl 2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl2-[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl 2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate;

Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxymethylether-butanoate;

Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoate;

Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acrylate;

Methyl2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylacetate;

Methyl2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate;

Methyl2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-benzyloxypropanoate;

Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoate;

Methyl2-[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)]pentanoate;

Methyl2-[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoate;

Methyl2-[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yn-oate;

Methyl2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate;

Ethyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate;

2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;

[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;

(2,3,6-Trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid;

(3-Ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid;

(2-Ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid;

2-(2,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid;

[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-(2,3,6-Trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid;

2-(3-Ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid;

2-(2,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid;

2-(2-Ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid;

2-[2-Methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

(2S)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

(2R)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-(3,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid;

2-(6-Methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid;

2-[2-Methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoic acid;

3-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]dihydrofuran-2(3H)-one;

2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoicacid;

2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylaceticacid;

2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acrylicacid;

2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoicacid;

2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-methyl-7-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoicacid;

2-[2-Methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoicacid;

2-[2-Methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid;

2-[2-Methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoicacid;

2-[2-Methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yn-oicacid;

2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

2-[2-Methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoateammonium salt;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoicacid;

2-[7-Benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid;

2-[2,7-Dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid;

2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoicacid;

N-cyano-2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide;

2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide;

Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate;

2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyaceticacid;

Methyl2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanenitrile;

2-Methyl-4-(p-tolyl)-3-[1-(1H-tetrazol-5-yl)butyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine;

Methyl2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

3-(1-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]butyl)-1,2,4-oxadiazol-5(4H)-one;

Ethyl[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Ethyl2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;

5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butyl]thiazolidine-2,4-dione;

Ethyl(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate;

Methyl2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Methyl2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Methyl2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Methyl2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Methyl2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]methylphosphonate;

Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]butylphosphonate;

1-(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butylphosphonicacid;

Methyl2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

Ethyl[7-acetyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;

[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoateammonium salt;

[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,6-diaza-fluoren-3-yl]pentanoateammonium salt;

[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,8-diaza-fluoren-3-yl]pentanoateammonium salt;

Methyl2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;

2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;

2-[2-methyl-4-(phenylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid.

[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;

[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;

[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;

Methyl2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;

2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid; and

2-[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid.

In a particular embodiment of all the formulae, embodiments and claimsherein whenever applicable, R¹ is selected from substituted orunsubstituted aryl, heteroaryl, C₁-C₆ alkyl, —O-aryl, —S-aryl, —NH-aryl,—O-heterocycle, —S-heterocycle, —NH-heterocycle (preferably from aryl orheteroaryl), and yet in a more particular embodiment is selected fromphenyl, —O-phenyl, —S-phenyl, —NH-phenyl, pyridinyl, furanyl,thiophenyl, indolyl, benzofuranyl, t-butyl, and benzo[d][1,3]dioxolyl(preferably benzo[d][1,3]dioxol-5-yl), preferably R¹ is selected fromphenyl, wherein said aryl, heteroaryl, C₁-C₆ alkyl, —O-aryl, —S-aryl,and —NH-aryl (preferably from aryl or heteroaryl), or more particularlyphenyl, —O-phenyl, —S-phenyl, —NH-phenyl, pyridinyl, furanyl,thiophenyl, indolyl, benzofuranyl, t-butyl, and benzo[d][1,3]dioxolyl(preferably benzo[d][1,3]dioxol-5-yl), preferably phenyl, can beunsubstituted or substituted, in a particular embodiment substitutedwith Z¹. Preferably, R¹ is selected from phenyl, tolyl, chlorophenyl,dichlorophenyl, fluorophenyl, trifluoromethylphenyl, ethylphenyl,methoxyphenyl, dimethoxyphenyl, trifluoromethoxyphenyl, pyridinyl,furanyl, thiophenyl, indolyl, benzofuranyl, t-butyl, andbenzo[d]dioxolyl (preferably benzo[d][1,3]dioxol-5-yl).

In another particular embodiment of all the formulae, embodiments andclaims herein, R¹ is substituted phenyl, in a particular embodimentsubstituted with one or more Z¹. Preferably R¹ is phenyl substitutedwith one or more groups selected from methyl, ethyl, chloro, fluoro,trifluoromethyl, hydroxyl, and methoxy. More preferably, R¹ is p-tolyl,unsubstituted or substituted with one or more Z¹. More particularly, R¹is o-hydroxy-p-tolyl.

In a yet more particular embodiment of the formulae, embodiments andclaims herein, R¹ is independently selected from arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; orheterocycle-alkynyl;

-   -   wherein said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl,        optionally includes one or more heteroatoms in the alkyl,        alkenyl or alkynyl moiety, said heteroatoms being selected from        the atoms O, S and N;    -   and wherein said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl,        can be unsubstituted or substituted with one or more Z¹;    -   and wherein two or more hydrogen atoms on a carbon atom or        heteroatom of said arylalkyl, arylalkenyl, arylalkynyl,        heterocycle-alkyl, heterocycle-alkenyl, or heterocycle-alkynyl        can be taken together to form a C═O, C═S, N═O, N═S, S═O or        S(O)₂.

In another particular embodiment, R1 is selected from —O-aryl, —S-aryl,—NH-aryl, —O-heterocycle, —S-heterocycle and —NH-heterocycle.

In another particular embodiment of all the formulae, claims andembodiments herein, one of R^(2a) and R^(2b) is not hydrogen.Preferably, one of R^(2a) and R^(2b) is hydrogen and the other one isselected from the group consisting of C₁-C₆ alkyl and C₁-C₆-alkoxy, morepreferably selected from the group consisting of C₁-C₄ alkyl andC₁-C₄-alkoxy, preferably n-propyl and butoxy, or one of R^(2a) andR^(2b) is hydrogen and the other one is taken together with R³ to form agamma-lactone radical, preferably a dihydrofuran-2(3H)-one radical.

In yet another particular embodiment of all the formulae, claims andembodiments herein, R³ is selected from —COOH, COOalkyl (preferably—COOMe or —COOEt, more preferably —COOMe), —CN, —C(O)NH₂, —C(O)NH(CN),—P(O)OH₂;

preferably R³ is —COOH or —COOalkyl (preferably —COOMe or —COOEt, morepreferably —COOMe), more preferably R³ is —COOH.

In yet another particular embodiment of all the formulae, claims andembodiments herein, R⁴ is selected from hydrogen, hydroxyl, alkyl oraryl, wherein said alkyl and aryl can be unsubstituted or substituted,in a particular embodiment substituted with Z¹. Preferably, R⁴ isselected from preferably hydrogen, alkyl or aryl, wherein said alkyl andaryl can be unsubstituted or substituted, in a particular embodimentsubstituted with Z¹. More preferably, R⁴ is selected from C₁-C₄ alkyl,even more preferably R⁴ is methyl.

In still another embodiment of all the formulae, claims and embodimentsherein, R⁵ and R⁶ are taken together to form a 5, 6 or 7-memberedunsaturated ring together with the carbon atoms to which they areattached;

-   -   wherein said 5, 6 or 7-membered unsaturated ring optionally        includes one or more heteroatoms, said heteroatoms being        selected from the atoms O, S and N;    -   and wherein said 5, 6 or 7-membered unsaturated ring can be        unsubstituted or substituted with one or more Z¹ as defined        herein;

and wherein two or more hydrogen atoms on a carbon atom or heteroatom ofsaid 5, 6 or 7-membered unsaturated ring can be taken together to form aC═O, C═S, N═O, N═S, S═O or S(O)₂, preferably with the proviso that theC═O is not adjacent to a N atom in a 6-membered ring, more particularlytwo or more hydrogen atoms on a carbon atom or heteroatom of said 5, 6or 7-membered unsaturated ring can be taken together to form a C═S, N═O,N═S, S═O or S(O)₂.

According to a second aspect, the invention relates to the compounds asdescribed herein for use as a medicament or a medicine, more inparticular for use as an antiviral medicament and for the use in theprevention or treatment of a viral infection in a subject (animal,mammal or human).

The present invention also relates to the use of compounds of theformula (including but not limited to A, B and C) and claims herein asantiviral compounds, more particularly as compounds active againstretroviruses, yet more in particular against HIV. The invention alsorelates to the use of the compounds of the invention for the manufactureof a medicament or as a pharmaceutically active ingredient, especiallyas a virus replication inhibitor, for instance for the manufacture of amedicament or pharmaceutical composition having antiviral activity forthe prevention and/or treatment of viral infections in humans, mammalsand animals in general. The present invention further relates to amethod of prevention or treatment of a viral infection, preferably aretroviral infection in an animal, including mammals, including a human,comprising administering to the animal in need of such treatment atherapeutically effective amount of a compound of the invention as anactive ingredient, preferably in admixture with at least apharmaceutically acceptable carrier.

Another aspect of the invention further relates to methods for thepreparation of compounds of formulae and claims herein. Also theintermediates used in the preparation methods described herein areaspects of the present invention.

One embodiment relates to a method for the preparation of the compoundsaccording to the invention comprising the steps of:

-   -   reacting a beta-ketonitile of formula R¹—C(O)CH₂CN with a        compound of formula R⁶C(O)CH₂R⁵ in the presence of sulfur and a        strong base in a polar protic solvent or in a polar aprotic        solvent at a temperature between 60° C. to 100° C.;    -   reacting the obtained 2-aminothiophene reaction product of the        previous step with a compound of formula R⁴C(O)CH₂CH₂R³ in the        presence of trimethyl chlorosilane in a polar aprotic solvent at        a temperature between 50° C. and 200° C.;    -   optionally, reacting the compound obtained in the previous step        with a compound having a structure of the formula R^(2a)—X        and/or R^(2b)—X through a nucleophilic substitution (wherein X        is a leaving group)

Another embodiment relates to a method for the preparation of thecompounds according to the invention comprising the steps of:

-   -   reacting a cyanoacetate derivative of formula ROC(O)CH₂CN with a        compound of formula R⁶C(O)CH₂R⁵ in the presence of sulfur and a        strong base in a polar protic solvent or in a polar aprotic        solvent at a temperature between 20° C. to 100° C.;    -   reacting the previously obtained        2-amino-4,5-disubstituted-thiophene-3-carboxylate derivative        with a compound of formula R4C(═CHCOOZ²)OZ² in an a polar        aprotic solvent at a temperature between 80° C. and 140° C. to        obtain an enamine intermediate which undergoes an intramolecular        ring cyclization in the presence of a strong base in a polar        protic solvent to provide a        5,6-substituted-4-hydroxythieno[2,3-b]pyridine-5-carboxylate        derivative;    -   the 4-hydroxyl function can then be converted to an halogen with        standard procedures know to the skilled in the art;    -   the ester function can then be reduced to a primary alcohol        which is immediately oxidized into an aldehyde following        standard procedures known to the skilled in the art;    -   the        5,6-substituted-4-halogenothieno[2,3-b]pyridine-5-carbaldehyde        derivative is then converted into a        2-(5,6-substituted-4-halogenothieno[2,3-b]pyridin-5-yl)-2-hydroxyacetate        derivative using an addition of trimethylsilylcyanide in the        presence of zinc iodide followed by hydrolysis in acidic        conditions;    -   the R^(2a) and or R^(2b) residues can then be introduced        following procedures known to the skilled in the art;    -   substituting the 4-halogen atom from the previously obtained        compound in a specific manner (amination, alkylation, arylation)        with suitable chemical reagents to obtain the desired compounds;    -   hydrolyzing the ester compounds obtained in the previous step to        obtain the desired free carboxylic acid derivatives.

Yet another aspect of the present invention relates to pharmaceuticalcompositions comprising the compounds of the invention according toformulae and claims herein in admixture with at least a pharmaceuticallyacceptable carrier, the active ingredient preferably being in aconcentration range of about 0.1 to 100% by weight, and to the use ofthese derivatives namely as drugs useful for the treatment of subjectssuffering from a viral infection, in particular a retroviral infection.

The invention further relates to the use of a composition comprising (a)one or more compounds of the invention (of formulae and claims herein),and (b) one or more viral inhibitors as biologically active agents inrespective proportions such as to provide a synergistic effect against aviral infection in a mammal, for instance in the form of a combinedpreparation for simultaneous, separate or sequential use in viralinfection therapy. Within the framework of this embodiment of theinvention, the viral enzyme inhibitors used as a therapeutically activeingredients (b) may belong to categories already known in the art. In aparticular embodiment, the compounds of the present invention can becombined with the following compounds:

-   -   nucleoside reverse transcriptase (RT) inhibitors such as, but        not limited to, azidothymidine (AZT), and lamivudine (3TC),    -   nucleotide reverse transcriptase inhibitors such as, but not        limited to, tenofovir (R-PMPA),    -   non-nucleoside reverse transcriptase inhibitors such as, but not        limited to, nevirapine, efavirenz,    -   protease inhibitors such as, but not limited to, nelfinavir,        saquinavir, ritonavir and amprenavir,    -   fusion inhihitors such as enfuvirtide, or    -   integrase inhibitors such as raltegravir or elvitegravir.

More generally, the invention relates to the compounds of formulae,embodiments and claims herein being useful as agents having biologicalactivity or as diagnostic agents. Any of the uses mentioned with respectto the present invention may be restricted to a non-medical use, anon-therapeutic use, a non-diagnostic use, or exclusively an in vitrouse, or a use related to cells remote from an animal.

The invention further relates to the use of the compounds of theinvention as chemical tools for virology and biochemistry. Inparticular, they can be used as research tools to investigate HIVbiology.

DETAILED DESCRIPTION OF THE INVENTION

The terminology “which optionally includes one or more heteroatoms, saidheteroatoms being selected from the atoms consisting of O, S, and N” asused herein, refers to a group where one or more carbon atoms arereplaced by an oxygen, nitrogen or sulphur atom and thus includes,depending on the group to which is referred, heteroalkyl, heteroalkenyl,heteroalkynyl, cycloheteroalkyl, cycloheteroalkenyl, cycloheteroalkynyl,heteroaryl, arylheteroalkyl, heteroarylalkyl, heteroarylheteroalkyl,arylheteroalkenyl, heteroarylalkenyl, heteroarylheteroalkenyl,heteroarylheteroalkenyl, arylheteroalkynyl, heteroarylalkynyl,heteroarylheteroalkynyl, among others. In other words, this term meansthat —CH₃ can be replaced by NH₂, —CH₂— by —NH—, —O— or —S—, a —CH═ by—N═ and ≡CH by ≡N. This term therefore comprises, depending on the groupto which is referred, as an example alkoxy, alkenyloxy, alkynyloxy,alkyl-O-alkylene, alkenyl-O-alkylene, arylalkoxy, benzyloxy,heterocycle-heteroalkyl, heterocycle-alkoxy, among others. As anexample, the terminology “alkyl which optionally includes one or moreheteroatoms, said heteroatoms being selected from the atoms consistingof O, S, and N” therefore refers to heteroalkyl, meaning an alkyl whichcomprises one or more heteroatoms in the hydrocarbon chain, whereas theheteroatoms may be positioned at the beginning of the hydrocarbon chain,in the hydrocarbon chain or at the end of the hydrocarbon chain.Examples of heteroalkyl include methoxy, methylthio, ethoxy, propoxy,CH₃—O—CH₂—, CH₃—S—CH₂—, CH₃—CH₂—O—CH₂—, CH₃—NH—, (CH₃)₂—N—,(CH₃)₂—CH₂—NH—CH₂—CH₂—, among many other examples. As an example, theterminology “arylalkyl which optionally includes one or more heteroatomsin the alkyl chain, said heteroatoms being selected from the atomsconsisting of O, S, and N” therefore refers to arylheteroalkyl, meaningan arylalkyl which comprises one or more heteroatoms in the hydrocarbonchain, whereas the heteroatoms may be positioned at the beginning of thehydrocarbon chain, in the hydrocarbon chain or at the end of thehydrocarbon chain. “Arylheteroalkyl” thus includes aryloxy, arylalkoxy,aryl-alkyl-NH— and the like and examples are phenyloxy, benzyloxy,aryl-CH₂—S—CH₂—, aryl-CH₂—O—CH₂—, aryl-NH—CH₂— among many otherexamples. The same counts for “heteroalkenyl”, “heteroalkynyl”, andother terms used herein when referred to “which optionally includes oneor more heteroatoms, said heteroatoms being selected from the atomsconsisting of O, S, and N”. As used herein and unless otherwise stated,the expression “wherein said 5, 6 or 7-membered unsaturated ringoptionally includes one or more heteroatoms, said heteroatoms beingselected from the atoms O, S and N” means any 5, 6 or 7-memberedunsaturated cycloalkyl moiety, any 5, 6 or 7-membered aryl moiety, andany 5, 6 or 7-membered mono-unsaturated, multi-unsaturated or aromaticO, S and/or N containing heterocycle.

The terminology regarding a chemical group “wherein optionally two ormore hydrogen atoms on a carbon atom or heteroatom of said group can betaken together to form a C═O, C═S, N═O, N═S, S═O or S(O)₂” as usedherein, refers to a group where two or more hydrogen atoms on a carbonatom or heteroatom of said group are taken together to form C═O, C═S,N═O, N═S, S═O or S(O)₂. In other words, the expression means that acarbon atom or heteroatom of said group can be oxidized to form a C═O,C═S, N═O, N═S, S═O or S(O)₂. As an example, the terminology refers to“an alkyl wherein optionally two or more hydrogen atoms on a carbon atomor heteroatom of said alkyl can be taken together to form a C═O, C═S,N═O, N═S, S═O or S(O)₂”, includes among other examples CH₃—C(O)—CH₂—,CH₃—C(O)—, CH₃—C(S)—CH₂— and (CH₃)₂—CH₂—C(O)—CH₂—CH₂—. Therefore, asused herein and unless otherwise stated, the expression “two or morehydrogen atoms on a carbon atom or heteroatom of said 5, 6 or 7-memberedunsaturated ring can be taken together to form a C═O, C═S, N═O, N═S, S═Oor S(O)₂” means that a carbon atom or heteroatom of the ring can beoxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂.

The combination for a group “which optionally includes one or moreheteroatoms, said heteroatoms being selected from the atoms consistingof O, S, and N” and “wherein optionally two or more hydrogen atoms on acarbon atom or heteroatom of said group can be taken together to form aC═O, C═S, N═O, N═S, S═O or S(O)₂” can combine the two aspects describedherein above and includes, if the group referred to is alkyl, amongother examples CH₃—COO—, CH₃—COO—CH₂—, CH₃—NH—CO—, CH₃—NH—CO—CH₂—,CH₃—NH—CS—CH₂—, CH₃—NH—CS—NH—CH₂—, CH₃—NH—S(O)₂— andCH₃—NH—S(O)₂—NH—CH₂—.

The term “leaving group” as used herein means a chemical group which issusceptible to be displaced by a nucleophile or cleaved off orhydrolysed in basic or acidic conditions. In a particular embodiment, aleaving group is selected from a halogen atom (e.g., Cl, Br, I) or asulfonate (e.g., mesylate, tosylate, triflate).

The term “alkyl” as used herein means C₁-C₁₈ normal, secondary, ortertiary, linear or cyclic, branched or straight hydrocarbon with nosite of unsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl,1-butyl, 2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl(t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl. In a particular embodiment, the term alkyl refers to C₁₋₁₂hydrocarbons, yet more in particular to C₁₋₆ hydrocarbons as furtherdefined herein above.

The term “linear alkyl” as used herein means C₁-C₁₈ normal, secondary,or tertiary, linear, branched or straight, hydrocarbon with no site ofunsaturation. Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,2-methyl-1-propyl (i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl (t-Bu),1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl,3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl,3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl and3,3-dimethyl-2-butyl.

As used herein and unless otherwise stated, the term “cycloalkyl” meansa monocyclic saturated hydrocarbon monovalent radical having from 3 to10 carbon atoms, such as for instance cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, or aC₇₋₁₀ polycyclic saturated hydrocarbon monovalent radical having from 7to 10 carbon atoms such as, for instance, norbornyl, fenchyl,trimethyltricycloheptyl or adamantyl.

The term “alkenyl” as used herein is C₂-C₁₈ normal, secondary ortertiary, linear or cyclic, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp2 double bond. Examples include, but are not limitedto: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), cyclohexenyl (—C₆H₉) and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂). Thedouble bond may be in the cis or trans configuration. In a particularembodiment, the term alkenyl refers to C₁₋₁₂ hydrocarbons, yet more inparticular to C₁₋₆ hydrocarbons as further defined herein above.

The term “linear alkenyl” as used herein refers to C₂-C₁₈ normal,secondary or tertiary, linear, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp2 double bond. Examples include, but are not limitedto: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂) and 5-hexenyl(—CH₂CH₂CH₂CH₂CH═CH₂). The double bond may be in the cis or transconfiguration.

The term “cycloalkenyl” as used herein refers to C₂-C₁₈ normal,secondary or tertiary, cyclic hydrocarbon with at least one site(usually 1 to 3, preferably 1) of unsaturation, namely a carbon-carbon,sp2 double bond. Examples include, but are not limited to: cyclopentenyl(—C₅H₇) and cyclohexenyl (—C₆H₉). The double bond may be in the cis ortrans configuration.

The term “alkynyl” as used herein refers to C₂-C₁₈ normal, secondary,tertiary, linear or cyclic, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp triple bond. Examples include, but are not limited to:acetylenic (—C≡CH) and propargyl (—CH₂C≡CH). In a particular embodiment,the term alkenyl refers to C₁₋₁₂ hydrocarbons, yet more in particular toC₁₋₆ hydrocarbons as further defined herein above.

The term “linear alkynyl” as used herein refers to C₂-C₁₈ normal,secondary, tertiary, linear, branched or straight hydrocarbon with atleast one site (usually 1 to 3, preferably 1) of unsaturation, namely acarbon-carbon, sp triple bond. Examples include, but are not limited to:acetylenic (—C≡CH) and propargyl (—CH₂C≡CH).

The term “cycloalkynyl” as used herein refers to C₂-C₁₈ normal,secondary, tertiary, cyclic hydrocarbon with at least one site (usually1 to 3, preferably 1) of unsaturation, namely a carbon-carbon, sp triplebond. Examples include, but are not limited to: cyclohex-1-yne andethylene-cyclohex-1-yne.

The terms “alkylene” as used herein each refer to a saturated, branchedor straight chain hydrocarbon radical of 1-18 carbon atoms (more inparticular 1-12 or 1-6 carbon atoms), and having two monovalent radicalcenters derived by the removal of two hydrogen atoms from the same ortwo different carbon atoms of a parent alkane. Typical alkylene radicalsinclude, but are not limited to: methylene (—CH₂—) 1,2-ethyl (—CH₂CH₂—),1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like.

The term “aryl” as used herein means a aromatic hydrocarbon radical of6-20 carbon atoms derived by the removal of hydrogen from a carbon atomof a parent aromatic ring system. Typical aryl groups include, but arenot limited to 1 ring, or 2 or 3 rings fused together, radicals derivedfrom benzene, naphthalene, anthracene, biphenyl, and the like. In aparticular embodiment, the term “parent aromatic ring system” means amonocyclic aromatic ring system or a bi- or tricyclic ring system ofwhich at least one ring is aromatic. Therefore, in this embodiment,typical aryl groups include, but are not limited to 1 ring, or 2 or 3rings fused together, radicals derived from benzene, naphthalene,anthracene, biphenyl, 2,3-dihydro-1H-indenyl,5,6,7,8-tetrahydronaphthalenyl, 1,2,6,7,8,8a-hexahydroacenaphthylenyl,1,2-dihydroacenaphthylenyl, and the like.

“Arylalkyl” as used herein refers to an alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp3carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkylmoiety of the arylalkyl group is 1 to 6 carbon atoms and the aryl moietyis 5 to 14 carbon atoms.

“Arylalkenyl” as used herein refers to an alkenyl radical in which oneof the hydrogen atoms bonded to a carbon atom, is replaced with an arylradical. The arylalkenyl group comprises 6 to 20 carbon atoms, e.g. thealkenyl moiety of the arylalkenyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

“Arylalkynyl” as used herein refers to an alkynyl radical in which oneof the hydrogen atoms bonded to a carbon atom, is replaced with an arylradical. The arylalkynyl group comprises 6 to 20 carbon atoms, e.g. thealkynyl moiety of the arylalkynyl group is 1 to 6 carbon atoms and thearyl moiety is 5 to 14 carbon atoms.

The term “heterocycle” as used herein means a saturated, unsaturated oraromatic ring system including at least one N, O, S, or P. Heterocyclethus include heteroaryl groups. Heterocycle as used herein includes byway of example and not limitation these heterocycles described inPaquette, Leo A. “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; Katritzky, Alan R., Rees, C. W. and Scriven, E.“Comprehensive Heterocyclic Chemistry” (Pergamon Press, 1996); and J.Am. Chem. Soc. (1960) 82:5566. In a particular embodiment, the termmeans pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl),thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl,tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,benzothienyl, benzothiazolyl, isatinoyl,2,3-dihydropyrano[4,3,2-de]quinolinyl, chromanyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinolinyl and2,3-dihydrobenzofuranyl, preferably it means pyridyl, dihydroypyridyl,tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfuroxidized tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl,indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl,bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl,6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl,isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl,isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl,isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl,acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl,isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl,benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl,and isatinoyl.

“Heterocycle-alkyl” as used herein refers to an alkyl radical in whichone of the hydrogen atoms bonded to a carbon atom, typically a terminalor sp3 carbon atom, is replaced with a heterocyle radical. An example ofa heterocycle-alkyl group is 2-pyridyl-methylene. The heterocycle-alkylgroup comprises 6 to 20 carbon atoms, e.g. the alkyl moiety of theheterocycle-alkyl group is 1 to 6 carbon atoms and the heterocyclemoiety is 5 to 14 carbon atoms.

“Heterocycle-alkenyl” as used herein refers to an alkenyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith an heterocycle radical. The heterocycle-alkenyl group comprises 6to 20 carbon atoms, e.g. the alkenyl moiety of the heterocycle-alkenylgroup is 1 to 6 carbon atoms and the heterocycle moiety is 5 to 14carbon atoms.

“Heterocycle-alkynyl” as used herein refers to an alkynyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith a heterocycle radical. The heterocycle-alkynyl group comprises 6 to20 carbon atoms, e.g. the alkynyl moiety of the heterocycle-alkynylgroup is 1 to 6 carbon atoms and the heterocycle moiety is 5 to 14carbon atoms.

“Heteroaryl” means means an aromatic ring system including at least oneN, O, S, or P. Examples of heteroaryl include but are not limited topyridyl, dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.

“Heteroaryl-alkyl” as used herein refers to an alkyl radical in whichone of the hydrogen atoms bonded to a carbon atom, typically a terminalor sp3 carbon atom, is replaced with a heterocyle radical. An example ofa heteroaryl-alkyl group is 2-pyridyl-methylene. The heteroaryl-alkylgroup comprises 6 to 20 carbon atoms, e.g. the alkyl moiety of theheteroaryl-alkyl group is 1 to 6 carbon atoms and the heteroaryl moietyis 5 to 14 carbon atoms.

“Heteroaryl-alkenyl” as used herein refers to an alkenyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith an heteroaryl radical. The heteroaryl-alkenyl group comprises 6 to20 carbon atoms, e.g. the alkenyl moiety of the heteroaryl-alkenyl groupis 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbonatoms.

“Heteroaryl-alkynyl” as used herein refers to an alkynyl radical inwhich one of the hydrogen atoms bonded to a carbon atom, is replacedwith a heteroaryl radical. The heteroaryl-alkynyl group comprises 6 to20 carbon atoms, e.g. the alkynyl moiety of the heteroaryl-alkynyl groupis 1 to 6 carbon atoms and the heteroaryl moiety is 5 to 14 carbonatoms.

By way of example, carbon bonded heterocyclic rings are bonded atposition 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of apyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran,thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5of an oxazole, imidazole or thiazole, position 3, 4, or 5 of anisoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine,position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 ofa quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Stillmore typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl,4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl,5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl,6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example, nitrogen bonded heterocyclic rings are bonded atposition 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

As used herein and unless otherwise stated, the terms “alkoxy”,“cycloalkoxy”, “aryloxy”, “arylalkyloxy”, “oxyheterocycle ring”,“thio-alkyl”, “thio-cycloalkyl”, “arylthio”, “arylalkylthio” and“thioheterocyce” refer to substituents wherein an alkyl radical,respectively a cycloalkyl, aryl, arylalkyl or heterocycle radical (eachof them such as defined herein), are attached to an oxygen atom or asulfur atom through a single bond, such as but not limited to methoxy,ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy,mercaptobenzyl and the like. The same definitions will apply for alkenyland alkynyl radicals in stead of alkyl.

As used herein and unless otherwise stated, the term halogen means anyatom selected from the group consisting of fluorine, chlorine, bromineand iodine.

Any substituent designation that is found in more than one site in acompound of this invention shall be independently selected.

Substituents optionally are designated with or without bonds. Regardlessof bond indications, if a substituent is polyvalent (based on itsposition in the structure referred to), then any and all possibleorientations of the substituent are intended.

The compounds of the invention optionally are bound covalently to aninsoluble matrix and used for affinity chromatography (separations,depending on the nature of the groups of the compounds, for examplecompounds with pendant aryl are useful in hydrophobic affinityseparations.

The compounds of the invention are employed for the treatment orprophylaxis of viral infections, more particularly retroviralinfections, in particular HIV infections. When using one or morecompounds of the invention and of the formulae as defined herein:

-   -   the compound(s) may be administered to the animal or mammal        (including a human) to be treated by any means well known in the        art, i.e. orally, intranasally, subcutaneously, intramuscularly,        intradermally, intravenously, intra-arterially, parenterally or        by catheterization.    -   the therapeutically effective amount of the preparation of the        compound(s), especially for the treatment of viral infections in        humans and other mammals, preferably is a retroviral replication        inhibiting amount of the formulae as defined herein and        corresponds to an amount which ensures a plasma level of between        1 μg/ml and 100 mg/ml, optionally of 10 mg/ml.

The present invention further relates to a method for preventing ortreating a viral infections in a subject or patient by administering tothe patient in need thereof a therapeutically effective amount of thethieno[2,3-b]pyridines of the present invention. The therapeuticallyeffective amount of the compound(s), especially for the treatment ofviral infections in humans and other mammals, preferably is a retroviralreplication inhibiting amount. The suitable dosage is usually in therange of 0.001 mg to 60 mg, optionally 0.01 mg to 10 mg, optionally 0.1mg to 1 mg per day per kg bodyweight for humans. Depending upon thepathologic condition to be treated and the patient's condition, the saideffective amount may be divided into several sub-units per day or may beadministered at more than one day intervals.

As is conventional in the art, the evaluation of a synergistic effect ina drug combination may be made by analyzing the quantification of theinteractions between individual drugs, using the median effect principledescribed by Chou et al. in Adv. Enzyme Reg. (1984) 22:27. Briefly, thisprinciple states that interactions (synergism, additivity, antagonism)between two drugs can be quantified using the combination index(hereinafter referred as Cl) defined by the following equation:

${CI}_{x} = {\frac{{ED}_{x}^{1c}}{{ED}_{x}^{1a}} + \frac{{ED}_{x}^{2c}}{{ED}_{x}^{2a}}}$

wherein ED_(x) is the dose of the first or respectively second drug usedalone (1a, 2a), or in combination with the second or respectively firstdrug (1c, 2c), which is needed to produce a given effect. The said firstand second drug have synergistic or additive or antagonistic effectsdepending upon Cl<1, Cl=1, or Cl>1, respectively.

Synergistic activity of the pharmaceutical compositions or combinedpreparations of this invention against viral infection may also bereadily determined by means of one or more tests such as, but notlimited to, the isobologram method, as previously described by Elion etal. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. inAntimicrob. Agents Chemother. (1984) 25:515-517, using EC₅₀ forcalculating the fractional inhibitory concentration (hereinafterreferred as FIC). When the minimum FIC index corresponding to the FIC ofcombined compounds (e.g., FIC_(x)+FIC_(y)) is equal to 1.0, thecombination is said to be additive; when it is between 1.0 and 0.5, thecombination is defined as subsynergistic, and when it is lower than 0.5,the combination is by defined as synergistic. When the minimum FIC indexis between 1.0 and 2.0, the combination is defined as subantagonisticand, when it is higher than 2.0, the combination is defined asantagonistic.

This principle may be applied to a combination of different antiviraldrugs of the invention or to a combination of the antiviral drugs of theinvention with other drugs that exhibit anti-HIV activity.

The invention thus relates to a pharmaceutical composition or combinedpreparation having synergistic effects against a viral infection andcontaining:

Either: A)

-   (a) a combination of two or more of the thieno[2,3-b]pyridine    derivatives of the present invention, and-   (b) optionally one or more pharmaceutical excipients or    pharmaceutically acceptable carriers,    for simultaneous, separate or sequential use in the treatment or    prevention of a retroviridae infection    or

B)

-   (c) one or more anti-viral agents, and-   (d) at least one of the thieno[2,3-b]pyridines derivatives of the    present invention, and-   (e) optionally one or more pharmaceutical excipients or    pharmaceutically acceptable carriers,    for simultaneous, separate or sequential use in the treatment or    prevention of a retroviridae infection.    -   Suitable anti-viral agents for inclusion into the synergistic        antiviral compositions or combined preparations of this        invention include, for instance, tenofovir, azidothymidine        (AZT), lamivudine (3TC), nevirapine, efavirenz, nelfinavir,        saquinavir, ritonavir, amprenavir, enfuvirtide, rlvitegravir or        elvitegravir.

The pharmaceutical composition or combined preparation with synergisticactivity against viral infection according to this invention may containthe thieno[2,3-b]pyridines derivatives of the present invention over abroad content range depending on the contemplated use and the expectedeffect of the preparation. Generally, the content of thethieno[2,3-b]pyridines derivatives of the present invention of thecombined preparation is within the range of 0.1 to 99.9% by weight,preferably from 1 to 99% by weight, more preferably from 5 to 95% byweight.

According to a particular embodiment of the invention, the compounds ofthe invention may be employed in combination with other therapeuticagents for the treatment or prophylaxis of retroviral infections, morepreferably HIV. The invention therefore relates to the use of acomposition comprising:

-   (a) one or more compounds of the formulae herein, and-   (b) one or more retroviral enzyme inhibitors as biologically active    agents in respective proportions such as to provide a synergistic    effect against a viral infection, particularly a retroviral    infection in a mammal, for instance in the form of a combined    preparation for simultaneous, separate or sequential use in viral    infection therapy, such as of HIV.

More generally, the invention relates to the compounds of formula (A)being useful as agents having biological activity (particularlyantiviral activity) or as diagnostic agents. Any of the uses mentionedwith respect to the present invention may be restricted to a non-medicaluse, a non-therapeutic use, a non-diagnostic use, or exclusively an invitro use, or a use related to cells remote from an animal.

Those of skill in the art will also recognize that the compounds of theinvention may exist in many different protonation states, depending on,among other things, the pH of their environment. While the structuralformulae provided herein depict the compounds in only one of severalpossible protonation states, it will be understood that these structuresare illustrative only, and that the invention is not limited to anyparticular protonation stat—any and all protonated forms of thecompounds are intended to fall within the scope of the invention.

The term “pharmaceutically acceptable salts” as used herein means thetherapeutically active non-toxic salt forms which the compounds offormulae herein are able to form. Therefore, the compounds of thisinvention optionally comprise salts of the compounds herein, especiallypharmaceutically acceptable non-toxic salts containing, for example,Na⁺, Li⁺, K⁺, NH4⁺, Ca²⁺ and Mg²⁺. Such salts may include those derivedby combination of appropriate cations such as alkali and alkaline earthmetal ions or ammonium and quaternary amino ions with an acid anionmoiety, typically a carboxylic acid. The compounds of the invention maybear multiple positive or negative charges. The net charge of thecompounds of the invention may be either positive or negative. Anyassociated counter ions are typically dictated by the synthesis and/orisolation methods by which the compounds are obtained. Typical counterions include, but are not limited to ammonium, sodium, potassium,lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof.It will be understood that the identity of any associated counter ion isnot a critical feature of the invention, and that the inventionencompasses the compounds in association with any type of counter ion.Moreover, as the compounds can exist in a variety of different forms,the invention is intended to encompass not only forms of the compoundsthat are in association with counter ions (e.g., dry salts), but alsoforms that are not in association with counter ions (e.g., aqueous ororganic solutions). Metal salts typically are prepared by reacting themetal hydroxide with a compound of this invention. Examples of metalsalts which are prepared in this way are salts containing Li⁺, Na⁺, andK⁺. A less soluble metal salt can be precipitated from the solution of amore soluble salt by addition of the suitable metal compound. Inaddition, salts may be formed from acid addition of certain organic andinorganic acids to basic centers, typically amines, or to acidic groups.Examples of such appropriate acids include, for instance, inorganicacids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like; or organicacids such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic (i.e.2-hydroxybenzoic), p-aminosalicylic and the like. Furthermore, this termalso includes the solvates which the compounds of formulae herein aswell as their salts are able to form, such as for example hydrates,alcoholates and the like. Finally, it is to be understood that thecompositions herein comprise compounds of the invention in theirunionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids, especially thenaturally-occurring amino acids found as protein components. The aminoacid typically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

The compounds of the invention also include physiologically acceptablesalts thereof. Examples of physiologically acceptable salts of thecompounds of the invention include salts derived from an appropriatebase, such as an alkali metal (for example, sodium), an alkaline earth(for example, magnesium), ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl).Physiologically acceptable salts of an hydrogen atom or an amino groupinclude salts of organic carboxylic acids such as acetic, benzoic,lactic, fumaric, tartaric, maleic, malonic, malic, isethionic,lactobionic and succinic acids; organic sulfonic acids, such asmethanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonicacids; and inorganic acids, such as hydrochloric, sulfuric, phosphoricand sulfamic acids. Physiologically acceptable salts of a compoundcontaining a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NX₄ ⁺ (wherein Xtypically is independently selected from H or a C₁-C₄ alkyl group).However, salts of acids or bases which are not physiologicallyacceptable may also find use, for example, in the preparation orpurification of a physiologically acceptable compound. All salts,whether or not derived from a physiologically acceptable acid or base,are within the scope of the present invention.

As used herein and unless otherwise stated, the term “enantiomer” meanseach individual optically active form of a compound of the invention,having an optical purity or enantiomeric excess (as determined bymethods standard in the art) of at least 80% (i.e. at least 90% of oneenantiomer and at most 10% of the other enantiomer), preferably at least90% and more preferably at least 98%.

The term “isomers” as used herein means all possible isomeric forms,including tautomeric and stereochemical forms, which the compounds offormulae herein may possess, but not including position isomers.Typically, the structures shown herein exemplify only one tautomeric orresonance form of the compounds, but the corresponding alternativeconfigurations are contemplated as well. Unless otherwise stated, thechemical designation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers (since the compounds of formulae hereinmay have at least one chiral center) of the basic molecular structure,as well as the stereochemically pure or enriched compounds. Moreparticularly, stereogenic centers may have either the R- orS-configuration, and multiple bonds may have either cis- ortrans-configuration.

Pure isomeric forms of the said compounds are defined as isomerssubstantially free of other enantiomeric or diastereomeric forms of thesame basic molecular structure. In particular, the term“stereoisomerically pure” or “chirally pure” relates to compounds havinga stereoisomeric excess of at least about 80% (i.e. at least 90% of oneisomer and at most 10% of the other possible isomers), preferably atleast 90%, more preferably at least 94% and most preferably at least97%. The terms “enantiomerically pure” and “diastereomerically pure”should be understood in a similar way, having regard to the enantiomericexcess, respectively the diastereomeric excess, of the mixture inquestion.

Separation of stereoisomers is accomplished by standard methods known tothose in the art. One enantiomer of a compound of the invention can beseparated substantially free of its opposing enantiomer by a method suchas formation of diastereomers using optically active resolving agents(“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGrawHill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).Separation of isomers in a mixture can be accomplished by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure enantiomers, or (3) enantiomers can be separated directlyunder chiral conditions. Under method (1), diastereomeric salts can beformed by reaction of enantiomerically pure chiral bases such asbrucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine(amphetamine), and the like with asymmetric compounds bearing acidicfunctionality, such as carboxylic acid and sulfonic acid. Thediastereomeric salts may be induced to separate by fractionalcrystallization or ionic chromatography. For separation of the opticalisomers of amino compounds, addition of chiral carboxylic or sulfonicacids, such as camphorsulfonic acid, tartaric acid, mandelic acid, orlactic acid can result in formation of the diastereomeric salts.Alternatively, by method (2), the substrate to be resolved may bereacted with one enantiomer of a chiral compound to form adiastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry ofOrganic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomericcompounds can be formed by reacting asymmetric compounds withenantiomerically pure chiral derivatizing reagents, such as menthylderivatives, followed by separation of the diastereomers and hydrolysisto yield the free, enantiomerically enriched xanthene. A method ofdetermining optical purity involves making chiral esters, such as amenthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemicmixture, and analyzing the NMR spectrum for the presence of the twoatropisomeric diastereomers. Stable diastereomers can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111). Under method (3), a racemic mixture of two asymmetricenantiomers is separated by chromatography using a chiral stationaryphase. Suitable chiral stationary phases are, for example,polysaccharides, in particular cellulose or amylose derivatives.Commercially available polysaccharide based chiral stationary phases areChiralCel™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD,AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use incombination with said polysaccharide chiral stationary phases are hexaneand the like, modified with an alcohol such as ethanol, isopropanol andthe like. (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed.Chapman and Hall, New York; Okamoto, (1990) “Optical resolution ofdihydropyridine enantiomers by High-performance liquid chromatographyusing phenylcarbamates of polysaccharides as a chiral stationary phase”,J. of Chromatogr. 513:375-378).

The terms cis and trans are used herein in accordance with ChemicalAbstracts nomenclature and include reference to the position of thesubstituents on a ring moiety. The absolute stereochemical configurationof the compounds of formula (1) may easily be determined by thoseskilled in the art while using well-known methods such as, for example,X-ray diffraction.

The compounds of the invention may be formulated with conventionalcarriers and excipients, which will be selected in accordance withstandard practice. Tablets will contain excipients, glidants, fillers,binders and the like. Aqueous formulations are prepared in sterile form,and when intended for delivery by other than oral administrationgenerally will be isotonic. Formulations optionally contain excipientssuch as those set forth in the “Handbook of Pharmaceutical Excipients”(1986) and include ascorbic acid and other antioxidants, chelatingagents such as EDTA, carbohydrates such as dextrin,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike.

Subsequently, the term “pharmaceutically acceptable carrier” as usedherein means any material or substance with which the active ingredientis formulated in order to facilitate its application or dissemination tothe locus to be treated, for instance by dissolving, dispersing ordiffusing the said composition, and/or to facilitate its storage,transport or handling without impairing its effectiveness. Thepharmaceutically acceptable carrier may be a solid or a liquid or a gaswhich has been compressed to form a liquid, i.e. the compositions ofthis invention can suitably be used as concentrates, emulsions,solutions, granulates, dusts, sprays, aerosols, suspensions, ointments,creams, tablets, pellets or powders.

Suitable pharmaceutical carriers for use in the said pharmaceuticalcompositions and their formulation are well known to those skilled inthe art, and there is no particular restriction to their selectionwithin the present invention. They may also include additives such aswetting agents, dispersing agents, stickers, adhesives, emulsifyingagents, solvents, coatings, antibacterial and antifungal agents (forexample phenol, sorbic acid, chlorobutanol), isotonic agents (such assugars or sodium chloride) and the like, provided the same areconsistent with pharmaceutical practice, i.e. carriers and additiveswhich do not create permanent damage to mammals. The pharmaceuticalcompositions of the present invention may be prepared in any knownmanner, for instance by homogeneously mixing, coating and/or grindingthe active ingredients, in a one-step or multi-steps procedure, with theselected carrier material and, where appropriate, the other additivessuch as surface-active agents. may also be prepared by micronisation,for instance in view to obtain them in the form of microspheres usuallyhaving a diameter of about 1 to 10 gm, namely for the manufacture ofmicrocapsules for controlled or sustained release of the activeingredients.

Suitable surface-active agents, also known as emulgent or emulsifier, tobe used in the pharmaceutical compositions of the present invention arenon-ionic, cationic and/or anionic materials having good emulsifying,dispersing and/or wetting properties. Suitable anionic surfactantsinclude both water-soluble soaps and water-soluble syntheticsurface-active agents. Suitable soaps are alkaline or alkaline-earthmetal salts, unsubstituted or substituted ammonium salts of higher fattyacids (C₁₀-C₂₂), e.g. the sodium or potassium salts of oleic or stearicacid, or of natural fatty acid mixtures obtainable from coconut oil ortallow oil. Synthetic surfactants include sodium or calcium salts ofpolyacrylic acids; fatty sulphonates and sulphates; sulphonatedbenzimidazole derivatives and alkylarylsulphonates. Fatty sulphonates orsulphates are usually in the form of alkaline or alkaline-earth metalsalts, unsubstituted ammonium salts or ammonium salts substituted withan alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. thesodium or calcium salt of lignosulphonic acid or dodecylsulphonic acidor a mixture of fatty alcohol sulphates obtained from natural fattyacids, alkaline or alkaline-earth metal salts of sulphuric or sulphonicacid esters (such as sodium lauryl sulphate) and sulphonic acids offatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazolederivatives preferably contain 8 to 22 carbon atoms. Examples ofalkylarylsulphonates are the sodium, calcium or alcoholamine salts ofdodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or anaphthalene-sulphonic acid/formaldehyde condensation product. Alsosuitable are the corresponding phosphates, e.g. salts of phosphoric acidester and an adduct of p-nonylphenol with ethylene and/or propyleneoxide, or phospholipids. Suitable phospholipids for this purpose are thenatural (originating from animal or plant cells) or syntheticphospholipids of the cephalin or lecithin type such as e.g.phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerine,lysolecithin, cardiolipin, dioctanylphosphatidyl-choline,dipalmitoylphoshatidyl-choline and their mixtures.

Suitable non-ionic surfactants include polyethoxylated andpolypropoxylated derivatives of alkylphenols, fatty alcohols, fattyacids, aliphatic amines or amides containing at least 12 carbon atoms inthe molecule, alkylarenesulphonates and dialkylsulphosuccinates, such aspolyglycol ether derivatives of aliphatic and cycloaliphatic alcohols,saturated and unsaturated fatty acids and alkylphenols, said derivativespreferably containing 3 to 10 glycol ether groups and 8 to 20 carbonatoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms inthe alkyl moiety of the alkylphenol. Further suitable non-ionicsurfactants are water-soluble soluble adducts of polyethylene oxide withpoylypropylene glycol, ethylenediaminopolypropylene glycol containing 1to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ethergroups. Such compounds usually contain from 1 to 5 ethyleneglycol unitsper propyleneglycol unit. Representative examples of non-ionicsurfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolicethers, polypropylene/polyethylene oxide adducts,tributylphenoxypolyethoxyethanol, polyethyleneglycol andoctylphenoxypolyethoxyethanol. Fatty acid esters of polyethylenesorbitan (such as polyoxyethylene sorbitan trioleate), glycerol,sorbitan, sucrose and pentaerythritol are also suitable non-ionicsurfactants.

Suitable cationic surfactants include quaternary ammonium salts,particularly halides, having 4 hydrocarbon radicals optionallysubstituted with halo, phenyl, substituted phenyl or hydroxy; forinstance quaternary ammonium salts containing as N-substituent at leastone C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyland the like) and, as further substituents, unsubstituted or halogenatedlower alkyl, benzyl and/or hydroxy-lower alkyl radicals.

A more detailed description of surface-active agents suitable for thispurpose may be found for instance in “McCutcheon's Detergents andEmulsifiers Annual” (MC Publishing Crop., Ridgewood, N.J., 1981),“Tensid-Taschenbucw’, 2 d ed. (Hanser Verlag, Vienna, 1981) and“Encyclopaedia of Surfactants, (Chemical Publishing Co., New York,1981).

Compounds of the invention and their physiologically acceptable salts(hereafter collectively referred to as the active ingredients) may beadministered by any route appropriate to the condition to be treated,suitable routes including oral, rectal, nasal, topical (includingocular, buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural). The preferred route of administration may vary with forexample the condition of the recipient.

While it is possible for the active ingredients to be administeredalone, it is preferable to present them as pharmaceutical formulations.The formulations, both for veterinary and for human use, of the presentinvention comprise at least one active ingredient, as above described,together with one or more pharmaceutically acceptable carriers thereforeand optionally other. therapeutic ingredients. The carrier(s) optimallyare “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof. The formulations include those suitable for oral, rectal,nasal, topical (including buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous, intradermal,intrathecal and epidural) administration. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. Such methods includethe step of bringing into association the active ingredient with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as solution or a suspension in an aqueous liquid ora non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. For infections of the eye or other external tissuese.g. mouth and skin, the formulations are optionally applied as atopical ointment or cream containing the active ingredient(s) in anamount of, for example, 0.075 to 20% w/w (including active ingredient(s)in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6%w/w, 0.7% w/w, etc), preferably 0.2 to 15% w/w and most preferably 0.5to 10% w/w. When formulated in an ointment, the active ingredients maybe employed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include, for example, at least 30% w/w of a polyhydric alcohol,i.e. an alcohol having two or more hydroxyl groups such as propyleneglycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethyleneglycol (including PEG400) and mixtures thereof. The topical formulationsmay desirably include a compound which enhances absorption orpenetration of the active ingredient through the skin or other affectedareas. Examples of such dermal penetration enhancers includedimethylsulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Optionally, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus the cream should optionally be anon-greasy, non-staining and washable product with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is optionally present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%particularly about 1.5% w/w. Formulations suitable for topicaladministration in the mouth include lozenges comprising the activeingredient in a flavored basis, usually sucrose and acacia ortragacanth; pastilles comprising the active ingredient in an inert basissuch as gelatin and glycerin, or sucrose and acacia; and mouthwashescomprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate. Formulations suitable for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns (including particle sizes in arange between 20 and 500 microns in increments of 5 microns such as 30microns, 35 microns, etc), which is administered in the manner in whichsnuff is taken, i.e. by rapid inhalation through the nasal passage froma container of the powder held close up to the nose. Suitableformulations wherein the carrier is a liquid, for administration as forexample a nasal spray or as nasal drops, include aqueous or oilysolutions of the active ingredient. Formulations suitable for aerosoladministration may be prepared according to conventional methods and maybe delivered with other therapeutic agents.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Preferred unit dosage formulations are those containing a daily dose orunit daily sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds of the invention can be used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient can be controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given invention compound. Controlled releaseformulations adapted for oral administration in which discrete unitscomprising one or more compounds of the invention can be preparedaccording to conventional methods.

Additional ingredients may be included in order to control the durationof action of the active ingredient in the composition. Control releasecompositions may thus be achieved by selecting appropriate polymercarriers such as for example polyesters, polyamino acids, polyvinylpyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose,carboxymethylcellulose, protamine sulphatesulphate and the like. Therate of drug release and duration of action may also be controlled byincorporating the active ingredient into particles, e.g. microcapsules,of a polymeric substance such as hydrogels, polylactic acid,hydroxymethylcellulose, polymethyl methacrylate and the otherabove-described polymers. Such methods include colloid drug deliverysystems like liposomes, microspheres, microemulsions, nanoparticles,nanocapsules and so on. Depending on the route of administration, thepharmaceutical composition may require protective coatings.Pharmaceutical forms suitable for injectionable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation thereof. Typical carriers for this purposetherefore include biocompatible aqueous buffers, ethanol, glycerol,propylene glycol, polyethylene glycol and the like and mixtures thereof.

In view of the fact that, when several active ingredients are used incombination, they do not necessarily bring out their joint therapeuticeffect directly at the same time in the mammal to be treated, thecorresponding composition may also be in the form of a medical kit orpackage containing the two ingredients in separate but adjacentrepositories or compartments. In the latter context, each activeingredient may therefore be formulated in a way suitable for anadministration route different from that of the other ingredient, e.g.one of them may be in the form of an oral or parenteral formulationwhereas the other is in the form of an ampoule for intravenous injectionor an aerosol.

Another embodiment of this invention relates to various precursor or“prodrug” forms of the compounds of the present invention. It may bedesirable to formulate the compounds of the present invention in theform of a chemical species which itself is not significantlybiologically-active, but which when delivered to the animal will undergoa chemical reaction catalyzed by the normal function of the body of theanimal, inter alia, enzymes present in the stomach or in blood serum,said chemical reaction having the effect of releasing a compound asdefined herein. The term “pro-drug” thus relates to these species whichare converted in vivo into the active pharmaceutical ingredient.

The prodrugs of the present invention can have any form suitable to theformulator, for example, esters are non-limiting common pro-drug forms.In the present case, however, the pro-drug may necessarily exist in aform wherein a covalent bond is cleaved by the action of an enzymepresent at the target locus. For example, a C—C covalent bond may beselectively cleaved by one or more enzymes at said target locus and,therefore, a pro-drug in a form other than an easily hydrolysableprecursor, inter alia an ester, an amide, and the like, may be used. Thecounterpart of the active pharmaceutical ingredient in the pro-drug canhave different structures such as an amino acid or peptide structure,alkyl chains, sugar moieties and others as known in the art.

For the purpose of the present invention the term “therapeuticallysuitable prodrug” is defined herein as “a compound modified in such away as to be transformed in vivo to the therapeutically active form,whether by way of a single or by multiple biological transformations,when in contact with the tissues of the animal, mammal or human to whichthe pro-drug has been administered, and without undue toxicity,irritation, or allergic response, and achieving the intended therapeuticoutcome “.

More specifically the term “prodrug”, as used herein, relates to aninactive or significantly less active derivative of a compound such asrepresented by the structural formula (I), which undergoes spontaneousor enzymatic transformation within the body in order to release thepharmacologically active form of the compound. For a comprehensivereview, reference is made to Rautio J. et al. (“Prodrugs: design andclinical applications” Nature Reviews Drug Discovery, 2008, doi:10.1038/nrd2468).

The compounds of the invention can be prepared while using a series ofchemical reactions well known to those skilled in the art, altogethermaking up the process for preparing said compounds and exemplifiedfurther. The processes described further are only meant as examples andby no means are meant to limit the scope of the present invention.

The compounds of interest having a general formula I can be prepared asoutlined in the general chemical scheme A.

In a first step, a beta-ketonitrile of formula II (commerciallyavailable or prepared by procedures known to the skilled in the art oras set forth in the examples below), can be reacted with a compound offormula III in the presence of sulfur (or in particular embodiment witha sulfur source such as p-dithiane-2,5-diol and2,5-dimethyl-2,5-dihydroxy-1,4-dithiane) and a strong base (e.g., DBU,morpholine, triethylamine, . . . ) in a polar protic solvent (e.g.,methanol, ethanol, propan-2-ol, . . . ) or in a polar aprotic solventsuch as DMF at a temperature raising from 60° C. to 100° C., to yieldthe expected 2-aminothiophene derivative of formula IV. More detailedsynthetic procedures can be found in the following reference (Journal ofMedicinal Chemistry, 49, (13), 2006, 3906-3915). In more specificembodiments, when R⁵ and R⁶ are hydrogens or when for example one of R⁵and R⁶ is a hydrogen, and the other of R⁵ and R⁶ is a alkyl (such asmethyl), p-dithiane-2,5-diol and 2,5-dialkyl-2,5-dihydroxy-1,4-dithiane(such as 2,5-dimethyl-2,5-dihydroxy-1,4-dithiane) can be used as asulfur source respectively.

The intermediate of formula IV can then be reacted with agamma-ketoester (commercially available or prepared by procedures knownto the skilled in the art or as set forth in the examples below) havinga general formula V in the presence of trimethyl chlorosilane in a polaraprotic solvent (e.g., DMF, DMAc, . . . ) at high temperature (mostpreferably 100° C.) to yield to the desired compounds having a generalformula VI. In a particular embodiment for the synthesis of thecompounds of the invention, Z² is an alkyl (ester protecting group) suchas methyl or ethyl. For the synthesis of compounds of the inventionwherein R³ is different from —COOH or —COOZ², the same procedure can beused as provided in scheme A whereby the compound of formula V isreplaced by R⁴C(O)CH₂CH₂R³ or R⁴C(O)CH₂CR^(2a)R^(2b)R³ (commerciallyavailable or prepared by procedures known to the skilled in the art).

Similarly, compounds having a general formula IX can be obtained fromcompounds IV and compounds VIII following a procedure identical to theone used for the preparation of compounds VI and described in thefollowing reference (Heterocycles 7 (11), 2397-2411, 2007). Compounds ofgeneral formula VII can be obtained from compounds with formula VI andderivatives R^(2a)X and/or R^(2b)X, wherein X is a leaving group such asa halogen atom (e.g., Cl, Br, I) or a sulfonate (e.g., mesylate,tosylate, triflate) following procedures that are known to the skilledin the art or as set forth in the examples below. Similarly, compoundsof general formula VII can also be obtained from intermediates offormula IV and intermediates of formula X (commercially available orprepared by procedures known to the skilled in the art or as set forthin the examples below). Compounds of formula VII can be finallyconverted into the desired carboxylic acid derivatives having a generalformula I by using standard basic hydrolysis conditions known to theskilled in the art or as set forth in the examples below.

In a first step, a cyanoacetate derivative of formula XI (commerciallyavailable or prepared by procedures known to the skilled in the art),wherein R is an ester protecting group (e.g., methyl, ethyl and thelike), can be reacted with a compound of formula III in the presence ofsulfur (or in particular embodiment with a sulfur source such asp-dithiane-2,5-diol and 2,5-dimethyl-2,5-dihydroxy-1,4-dithiane) and astrong base (e.g., DBU, morpholine, triethylamine, . . . ) in a polarprotic solvent (e.g., methanol, ethanol, propan-2-ol, . . . ) or in apolar aprotic solvent such as DMF at a temperature raising from 60° C.to 100° C., to yield the expected 2-aminothiophene derivative of formulaXII. More detailed synthetic procedures can be found in the followingreference (Journal of Medicinal Chemistry, 49, (13), 2006, 3906-3915).In more specific embodiments, when R⁵ and R⁶ are hydrogens or when forexample one of R⁵ and R⁶ is a hydrogen, and the other of R⁵ and R⁶ is aalkyl (such as methyl), p-dithiane-2,5-diol and2,5-dialkyl-2,5-dihydroxy-1,4-dithiane (such as2,5-dimethyl-2,5-dihydroxy-1,4-dithiane) can be used as a sulfur sourcerespectively. Intermediates of formula XII can be reacted withintermediates of formula XIII (commercially available or synthesized byprocedures known to the skilled in the art) wherein Z² is an alkyl group(e.g., methyl, ethyl and the like) in an apolar aprotic solvent (e.g.,benzene, toluene, xylene and the like) at a temperature raising from 80to 140° C. to provide enamine intermediates which are converted intointermediates of general formula XIV in the presence of a strong base(e.g., sodium hydride, sodium methoxide, sodium ethoxide, . . . ) in apolar protic solvent (e.g., alcohol, . . . ). Intermediates XIV are thenconverted in intermediates of formula XV by procedures known to theskilled in the art or as set forth in the examples below, and wherein LGis a leaving group only selected from halogen. It is known for theskilled in the art that when LG is a chlorine atom, this atom can beexchange for a more reactive halogen atom (bromine or iodine) usingsubstitution reactions which are known to the skilled in the art or asset forth in the examples below. Intermediates of formula XV can then beconverted into intermediates of formula XVI by reduction of the esterfunctionality using standard reducing agents (LiAlH₄ and most preferablyDIBAL) in polar aprotic solvents (e.g., THF, dichloromethane and thelike) at a temperature ranging from −78° C. to 0° C. (most preferably−78° C.). Intermediates of formula XVI are then oxidized inintermediates of formula XVII by procedures known to the skilled in theart or as set forth in the examples below. Addition oftrimethylsilylcyanide on intermediates XVII in the presence of zinciodide provides intermediates of formula XVIII, which are immediatelyhydrolyzed under acidic conditions to provide intermediates of formulaXIX. Intermediates of general formula XX may be obtained by reactingintermediates of formula XIX with suitable R^(2a)X and or R^(2b)X,wherein X is a leaving group such as a halogen atom (e.g., Cl, Br, I) ora sulfonate (e.g., mesylate, tosylate, triflate) in the presence of astrong base (e.g., NaH, LiHMDS, DBU and the like) in a polar aproticsolvent (e.g., THF, dichloromethane, DMF and the like) at a temperatureraising from −78° C. to 80° C. (most preferably −78° C.). Alternatively,compounds of general formula

XX may also be obtained in acidic conditions by reacting an alkene(e.g., ethylene, prolylene, isoprene and the like) or an alkeneprecursor (e.g., isopropyl acetate, tert-butyl acetate, and the like).In another embodiment, the hydroxyl function of intermediates XIX mayalso be converted into a leaving group selected from sulfonates (e.g.,mesylate, tosylate and the like) or from halogen atom (e.g., chlorine,bromine, iodine) following procedures known to the skilled in the art oras set forth in the examples below. This leaving group can then undergoa nucleophilic substitution using suitable precursors of R^(2a) and orR^(2b) following reactions which are known to the skilled in the art toprovide the desired intermediates of formula XX. Alternatively, thehydroxyl function of intermediates XIX may also be converted into a keto(C═) function following standard oxidation reactions which are known tothe skilled in the art. This keto function can then be subjected toreductive amination conditions to provide the desired intermediates offormula XX. Additionally, this keto function may undergo a nucleophilicattack using suitable precursors of R^(2a) and or R^(2b) followingreactions which are known to the skilled in the art to provide thedesired intermediates of formula XX. Coupling of intermediates XX with asuitable R¹ precursor by procedures known to the skilled in the art(amination, Suzuki coupling, Negishi coupling, Stille coupling and thelike) provides compounds of formula VII, which can be converted in thedesired compounds of formula I using standard hydrolysis conditions.

In a more specific embodiment, compounds of the present invention can beprepared as a pure enantiomeric form following the procedure depictedhereunder.

Racemic acids of general formula I are reacted with a chiral auxiliary*R in order to form a mixture of diastereomers XXIa and XXIb which arethen separable using different methods known to the skilled in the art(e.g., silica gel chromatography, crystallization, HPLC among others).It is known for the skilled in the art that many different chiralauxiliaries can be used to achieve chiral resolution of racemic acids.Most preferably, *R will be selected from enantiomerically pure alcohol(e.g., L(—)-menthol, L(−)-borneol, D(−)-pantolactone and the like) orfrom enatiomerically pure oxazolidinone derivatives (e.g.,(R)-(+)-4-Isopropyl-2-oxazolidinone, R-(+)-4-benzyl-2-oxazolidinone, andthe like). Pure enantiomers Ia and Ib can then be obtained aftercleavage of the chiral auxiliary by standard hydrolysis conditions knownto the skilled in the art or as set forth in the examples below.

In a particular embodiment, compounds of the invention, wherein R³ isdifferent from —COOH or —COOZ², can be prepared following reactionsknown to the skilled in the art or as depicted in the following chemicalschemes (scheme D to J).

Compounds of general formula XXII and XXIII can be obtained fromcompounds of general formula I by treatment with carbonyl diimidazole(CDI) and suitable sulfonamide derivatives. More detailed informationcan be found in J. Med. Chem. 2007, 50, 3984-4002 and J. Med. Chem.2002, 45, 567-583. Compounds of general formula I can be reacted withthionyl chloride in order to obtain an acid chloride intermediate whichis immediately substituted with cyanamide or ammonia to providecompounds of formula XXIV and XXV respectively. Compounds of formula XXVare subsequently converted in compounds of formula XXVI by treatmentwith trifluoroacetic anhydride (TFAA) in the presence of triethylamineas described in Tetrahedron, 2006 (62), 11948-11954. Compounds offormula XXVI can then be converted in compounds of general formula XXVIIfollowing a standard treatment by sodium azide in the presence ofammonium chloride. Compounds of general formula XXVIII can be obtainedfrom compounds of formula XXVI following a treatment with hydroxylamineand a ring closure reaction by addition of carbonyl diimidazole (CDI).

In a first step, intermediates of general formula XVII (see scheme B)are reacted with a suitable R¹ precursor by procedures known to theskilled in the art (Suzuki coupling, Negishi coupling, Stille couplingand the like) to provide intermediates of formula XXIX which areconverted in intermediates of formula XXX following standard reductionprocedures known to the skilled in the art. Reaction of compounds XXXwith diphenylphosphorylazide (DPPA) provide an azide intermediate whichis immediately reduced to furnish the desired intermediates of formulaXXXI.

Compounds of formula XXXII and XXXIII can be obtained from intermediatesXXXI following a procedure described in J. Heterocyclic Chem. 2006,43(2), 405-416. Compounds of general formula XXXIV can be obtained fromintermediates of formula XXX following the procedure described in US2004/0023921. Compounds of general formula XXXV can be obtained fromintermediates of formula XXIX following the procedure described in US2005/084488.

Compounds of formula XXXVI can be obtained from intermediates XXXfollowing a procedure described in Synthesis, 2006, 4131-4134. Compoundsof formula XXXVI can be converted into sulfonyl chloride derivatives bytreatment with phosphorus pentachloride or thionyl chloride which areimmediately converted in compounds of formula XXXVII by treatment withammonia. Compounds of formula XXXVIII and XXXIX can be obtained fromintermediates XXXVII following a procedure described in J. Med. Chem.2002, 45, 567-583.

Compounds of general formula I are converted in acid chloridederivatives of formula XL following procedures known to the skilled inthe art. Compounds of formula XLI and XLII can be obtained fromcompounds of general formula I and Meldrum's Acid following theconditions described in J. Org. Chem., 2000, 65, 1003-1007 and ChemischeBerichte, 1963, 96, 944-54 respectively.

The hydroxyl function of intermediates of formula XXX is converted in aleaving group following procedures known to the skilled in the art toprovide intermediates XLIII which are reacted with methyl3,3-dimethoxypropanoate to furnish the desired intermediates of formulaXLIV as described in Eur. J. Org. Chem., 2008, 10, 1753-1758. Compoundsof formula XLV are finally obtained by treatment with hydroxylamine asdescribed in Journal of the Chemical Society, Chemical Communications,1991, 5, 314-16.

The ester function of compounds of formula VII can be reduced to aprimary hydroxyl function which is subsequently oxidized in aldehydeusing a complex of pyridine-SO₃. The aldehyde is reacted withtrimethylsilylcyanide in the presence of zinc iodide and the resultingcondensation product is immediately hydrolyzed under acidic conditionsto provide intermediates of formula XLVI. Compounds of formula XLVII andXLVIII can be obtained from intermediates of formula XLVI following theprocedures described in WO2006/014262. Compounds of formula IL can beobtained from intermediates of formula XLVI following procedures knownfor the skilled in the art and described in J. Med. Chem., 1991, 34(9),2906-2916. Alternatively, compounds of formula VII can be reacted withtrimethylsilylcyanide in the presence of zinc iodide following anhydrolysis-esterification step to provide ester intermediates which areimmediately reduced into primary alcohol and finally oxidized to provideintermediates of general formula L. The final conversion ofintermediates of formula L into compounds of formula LI can be achievedfollowing the procedure described in J. Med. Chem., 2002, 45, 19-31.

Intermediates of formula XXIX are reacted with 1-(benzyloxy)-1H-pyrazole(commercially available or prepared according to the procedure describedin WO2006/108591) in the presence of butyl lithium to provideintermediates of formula LII. R^(2a) and or R^(2b) residues are thenintroduced following reactions known to the skilled in the art and thebenzyl protecting group is removed by treatment with triethylsilane inTFA to provide the desired compounds of formula LIII. More details canbe found in Bioorg. Med. Chem., 2007, 15, 3524-3538 and Tetrahedron,2002, 58, 2397-2404. Similarly, intermediates of formula XXIX arereacted with 1-(benzyloxy)-1H-imidazole (commercially available orprepared according to the procedure described in Synthesis, 1989, 10,773-775) in the presence of butyl lithium to provide intermediates offormula LIV. R^(2a) and or R^(2b) residues are then introduced followingreactions known to the skilled in the art and the benzyl protectinggroup is removed by treatment with triethylsilane in TFA. More detailscan be found in J. Org. Chem., 1998, 63, 7418-7420.

EXAMPLES

The following examples are provided for the purpose of illustrating thepresent invention and by no means should be interpreted to limit thescope of the present invention.

TABLE 1 Structures of example compounds of the invention and theirrespective codes. Cpd code STRUCTURE  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

Part A represents the preparation of the compounds (intermediates andfinal compounds) whereas Part B represents the pharmacological examples.

All the preparative HPLC purifications mentioned in this experimentalpart have been carried out with the following system: a Waters 2489UV/Visible Detector, a Waters 2545 Binary Gradient Module, a WatersFraction Collector III and a Waters Dual Flex Injector.

The separations were performed with a X-Bridge Prep C18, 100×19 mm,5 μmcolumn equipped with a X-Bridge C18, 5 μm, 19×10 mm Guard column.

Elutions were carried out with the gradient described in the followingtables, and detection wavelengths were fixed at 210 and 254nm:

HPLC Method 1:

Time Flow Rate Solvent Solvent (min) ml/min A % B % 0 20 50 50 2.00 2050 50 9.00 20 10 90 11.00 20 10 90 11.20 20 50 50 16.00 20 50 50 SolventA: Formic Acid LC-MS grade 0.1% in milliQ water Solvent B: AcetonitrileHPLC grade.

HPLC Method 2:

Time Flow Rate Solvent Solvent (min) (mL/min) A (%) B (%) 0 20 80 202.00 20 80 20 8.00 20 10 90 10.80 20 10 90 11.00 20 80 20 16.00 20 80 20Solvent A: Formic Acid LC-MS grade 0.1% in milliQ water Solvent B:Acetonitrile HPLC grade.

HPLC Method 3:

Time Flow Rate Solvent Solvent (min) (mL/min) A (%) B (%) 0 20 80 202.00 20 80 20 8.00 20 10 90 10.80 20 10 90 11.00 20 80 20 16.00 20 80 20Solvent A: Ammonium Acetate puriss p.a. for HPLC 10 mM in milliQ water,adjusted at pH 10 with Ammonium Hydroxyde puriss p.a. for HPLC. SolventB: Acetonitrile HPLC grade.

HPLC Method 4:

The HPLC apparatus is composed of : a Waters 2489 UV/Visible Detector, aWaters 2545 Binary Gradient Module, a Waters Dual Flex Injector. Theanalysis was performed with a ChiralPak IC 250×4.6 mm, 5 μm columnequipped with a ChiralPak IC, 10×4 mm, 5 μm, Guard Column. The detectionwavelengths were fixed at 210 and 254 nm and the elution were carriedout using an isocratic mode with a mixture ofn-Heptane/Isopropanol/TFA—75/25/0.1% as eluent.

Part A

-   Compounds with general formula IV have been prepared following    general procedure A unless otherwise described.-   Compounds with general formula VI have been prepared following    general procedure B unless otherwise described.-   Compounds with general formula VII have been prepared following    general procedure C unless otherwise described.

General Procedure A:

A mixture of a beta-ketonitrile (1 equivalent), a ketone (1 to 2equivalents), sulfur (1 to 2 equivalents) and morpholine (1 to 2equivalents) in ethanol (1 mL/mmol of default reagent) was heated to 60°C. in a sealed tube until disappearance of default compound. Aftercooling to room temperature, the reaction mixture was poured into waterand extracted with ethyl acetate. The organic layer was dried oversodium sulphatesulphate, filtered and concentrated under reducepressure. The residue was purified by flash chromatography on silica gelto afford the expected 1-(2-aminothiophen-3-yl)ketone derivative.

General Procedure B:

To a solution of (1-(2-aminothiophen-3-yl)ketone (1 equivalent) andmethyl levunilate (1 to 1.1 equivalent) in DMF (4 to 5 mL/mmol) placedin a safety pressure tube was slowly added chlorotrimethylsilane (4equivalents). The tube was sealed and heated at 100° C. for 18 h oruntil disappearance of the limiting reagent. After cooling to roomtemperature, the reaction mixture was partitioned between ethyl acetateand water. The organic phase was successively washed with a saturatedsolution of sodium hydrogen carbonate-water, brine, dried over sodiumsulphatesulphate, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel to afford theexpected methyl 2-(6-methylthieno[2,3-b]pyridin-5-yl)acetate.

General Procedure C:

To a solution of methyl 2-(6-methylthieno[2,3-b]pyridin-5-yl)acetate (1equivalent) in dry DMF at −10° C. was slowly added a 1N solution ofLHMDS in THF (1.1 to 2 equivalents). Then, the halide derivative (1.5 to2 equivalents) was added and the reaction mixture was stirred at roomtemperature for 3 to 18 h or until disappearance of the limitingreagent. The reaction mixture was quenched by addition of a saturatedsolution of ammonium chloride and the mixture was extracted with ethylacetate. The organic layer was washed with water, brine, dried oversodium sulphatesulphate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelto afford the desired product.

Example 1 Preparation of Intermediate(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.500 g; 3.141 mmol), cyclopentanone (0.278mL; 3.136 mmol), sulfur (0.101 g; 3.149 mmol), morpholine (0.275 mL;3.179 mmol) in ethanol (2.5 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-50%)in heptane furnished 0.524 g (65%) of the title compound as a yellowsolid.

ESI/APCI(+): 258 (M+H); 280 (M+Na).

ESI/APCI(−): 256 (M−H).

Example 2 Preparation of Intermediate(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)phenylmethanone

This intermediate was prepared according to the procedure A frombenzoylacetonitrile (0.725 g; 5 mmol), cyclopentanone (0.442 mL; 5mmol), sulfur (0.160 g; 5 mmol), morpholine (0.440 mL; 5 mmol) inethanol (5 mL) for 18 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (10-30%) in heptane furnished0.350 g (29%) of the title compound as a yellow solid.

ESI/APCI(+): 244 (M+H).

ESI/APCI(−): 242 (M−H).

Example 3 Preparation of Intermediate(2-Amino-4,5-dimethylthiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.200 g; 1.256 mmol), 2-butanone (0.213 mL;2.378 mmol), sulfur (0.081 g; 2.527 mmol), morpholine (0.221 mL; 2.554mmol) in ethanol (1.2 mL) for 40 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (5-25%) in heptanefurnished 0.171 g (55%) of the title compound as a yellow solid.

ESI/APCI(+): 246 (M+H); 268 (M+Na).

ESI/APCI(−): 244 (M−H).

Example 4 Preparation of Intermediate(2-Amino-4-ethyl-5-methylthiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.300 g; 1.885 mmol), 3-pentanone (0.400mL; 3.776 mmol), sulfur (0.121 g; 3.773 mmol), morpholine (0.329 mL;3.761 mmol) in ethanol (1.5 mL) for 40 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-25%)in heptane furnished 0.289 g (59%) of the title compound as a yellowsolid.

ESI/APCI(+): 260 (M+H); 272 (M+Na).

ESI/APCI(−): 258 (M−H).

Example 5 Preparation of Intermediate(2-Amino-5-ethyl-4-methylthiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.300 g; 1.885 mmol), 2-pentanone (0.202mL; 1.897 mmol), sulfur (0.066 g; 2.058 mmol), morpholine (0.187 mL;2.138 mmol) in ethanol (2 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-25%)in heptane furnished 0.304 g (62%) of the title compound as a yellowoil.

ESI/APCI(+): 260 (M+H); 282 (M+Na).

ESI/APCI(−): 258 (M−H).

Example 6 Preparation of Intermediate(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-chlorophenyl)methanone

This intermediate was prepared according to the procedure A from4-chlorobenzoylacetonitrile (0.300 g; 1.670 mmol), cyclopentanone (0.148mL; 1.670 mmol), sulfur (0.054 g; 1.684 mmol), morpholine (0.147 mL;1.699 mmol) in ethanol (1.4 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (15-60%)in heptane furnished 0.207 g (45%) of the title compound as a yellowsolid.

ESI/APCI(+): 278 (M+H).

ESI/APCI(−): 276 (M−H).

Example 7 Preparation of Intermediate(2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.500 g; 3.141 mmol), cyclohexanone (0.326mL; 3.146 mmol), sulfur (0.101 g; 3.149 mmol), morpholine (0.275 mL;3.179 mmol) in ethanol (3.5 mL) for 64 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-20%)in heptane furnished 0.776 g (91%) of the title compound as a yellowsolid.

ESI/APCI(+): 272 (M+H); 294 (M+Na).

ESI/APCI(−): 270 (M−H).

Example 8 Preparation of Intermediate(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-trifluoromethylphenyl)methanone

This intermediate was prepared according to the procedure A from4-trifluoromethylbenzoylacetonitrile (0.300 g; 1.407 mmol),cyclopentanone (0.125 mL; 1.410 mmol), sulfur (0.064 g; 1.996 mmol),morpholine (0.124 mL; 1.433 mmol) in ethanol (3 mL) for 64 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-25%) in heptane furnished 0.296 g (68%) of the titlecompound as a brown solid.

ESI/APCI(+): 312 (M+H).

ESI/APCI(−): 310 (M−H).

Example 9 Preparation of Intermediate(2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-ethylphenyl)methanone

This intermediate was prepared according to the procedure A from4-ethylbenzoylacetonitrile (0.300 g; 1.732 mmol), cyclopentanone (0.154mL; 1.737 mmol), sulfur (0.079 g; 2.463 mmol), morpholine (0.153 mL;1.768 mmol) in ethanol (3.6 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-50%)in heptane furnished 0.333 g (71%) of the title compound as a yellowsolid.

ESI/APCI(+): 272 (M+H).

ESI/APCI(−): 270 (M−H).

Example 10 Preparation of Intermediate(2-Amino-5-methylthiophen-3-yl)(p-tolyl)methanone

To a solution of 4-methylbenzoylacetonitrile (0.300 g; 1.885 mmol),sulfur (0.061 g; 1.902 mmol) and triethylamine (0.288 mL; 2.078 mmol) inDMF (4 mL) heated at 40° C. was added a solution of propionaldehyde(0.150 mL, 2.079 mmol) in ethanol (0.5 mL). The reaction mixture wasthen heated at 60° C. for 4 h. After cooling to room temperature, thereaction mixture was poured into water and extracted twice with ethylacetate. The organic layers were combined, washed with brine, dried oversodium sulphatesulphate, filtered and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gelusing a gradient of ethyl acetate (10-25%) in heptane to afford thetitle compound (0.317 g; 73%) as a yellow powder.

ESI/APCI(+): 232 (M+H); 254 (M+Na).

ESI/APCI(−): 230 (M−H).

Example 11 Preparation of Intermediate(2-Amino-4-methylthiophen-3-yl)(p-tolyl)methanone

To a suspension of 4-methylbenzoylacetonitrile (0.326 g; 2.048 mmol) and2,5-dimethyl-2,5-dihydroxy-1,4-dithiane (0.185 g; 1.026 mmol) in ethanol(4.3 mL) cooled at 0° C. was added triethylamine (0.284 mL; 2.049 mmol).After 10 min at room temperature, the reaction mixture was heated underreflux for 3 h. After cooling to room temperature, the reaction mixturewas partitioned between ethyl acetate and water. The organic phase waswashed with brine, dried over sodium sulphatesulphate, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel using a gradient of ethyl acetate (10-25%)in heptane to afford the title compound (0.157 g; 33%) as a yellowsolid.

ESI/APCI(+): 232 (M+H); 254 (M+Na).

ESI/APCI(−): 230 (M−H).

Example 12 Preparation of Intermediate(2-Aminothiophen-3-yl)(p-tolyl)methanone

To a suspension of 4-methylbenzoylacetonitrile (0.325 g; 2.042 mmol) andp-dithiane-2,5-diol (0.155 g; 1.018 mmol) in ethanol (4.3 mL) cooled at0° C. was added triethylamine (0.283 mL; 2.042 mmol). After 10 min atroom temperature, the reaction mixture was heated under reflux for 2 h.After cooling to room temperature, the reaction mixture was partitionedbetween ethyl acetate and water. The organic phase was washed withbrine, dried over sodium sulphatesulphate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel using a gradient of ethyl acetate (10-25%) in heptane toafford the title compound (0.288 g; 65%) as a yellow solid.

ESI/APCI(+): 218 (M+H).

ESI/APCI(−): 433 (2M−H).

Example 13 Preparation of IntermediateN-Boc(2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.477 g; 3 mmol),N-tert-Butyloxycarbonyl-4-piperidone (0.895 g; 4.5 mmol), sulfur (0.144g; 4.5 mmol), morpholine (0.382 mL; 4.5 mmol) in ethanol (3 mL) for 20h. Purification by flash chromatography on silica gel using a gradientof ethyl acetate (5-40%) in heptane furnished 1.1 g (99%) of the titlecompound as a bright yellow solid.

ESI/APCI(+): 373 (M+H).

Example 14 Preparation of Intermediate(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(2-furyl)methanone

This intermediate was prepared according to the procedure A from2-furoylacetonitrile (0.676 g, 5 mmol), cyclopentanone (0.66 mL, 7.50mmol), morpholine (0.65 mL, 7.50 mmol) and sulfur (0.240 g, 7.50 mmol)in ethanol (5 mL) for 36 h. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (5-40%) in heptanefurnished 0.440 g (38%) of the title compound as a yellow solid.

ESI/APCI(+): 234 (M+H).

ESI/APCI(−): 232 (M−H).

Example 15 Preparation of Intermediate(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(2-thienyl)methanone

This intermediate was prepared according to the procedure A from3-oxo-3-(2-thienyl)propionitrile (0.756 g, 5 mmol), cyclopentanone (0.66mL, 7.50 mmol), morpholine (0.65 mL, 7.50 mmol) and sulfur (0.240 g,7.50 mmol) in ethanol (5 mL) for 36 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-40%)in heptane furnished 0.510 g (41%) of the title compound as a yellowsolid.

ESI/APCI(+): 250 (M+H).

ESI/APCI(−): 248 (M−H).

Example 16 Preparation of Intermediate(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(p-anisyl)methanone

This intermediate was prepared according to the procedure A from4-methoxybenzoylacetonitrile (0.876 g, 5 mmol), cyclopentanone (0.66 mL,7.50 mmol), morpholine (0.65 mL, 7.50 mmol) and sulfur (0.240 g, 7.50mmol) in ethanol (5 mL) for 36 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (5-40%) in heptanefurnished 0.320 g (23%) of the title compound as a yellow solid.

ESI/APCI(+): 274 (M+H).

ESI/APCI(−): 272 (M−H).

Example 17 Preparation of Intermediate(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)tert-butylmethanone

A mixture of trimethylacetylacetonitrile (0.626 g, 5 mmol),cyclopentanone (0.66 mL, 7.50 mmol), morpholine (0.65 mL, 7.50 mmol) andsulfur (0.240 g, 7.50 mmol) in DMF (5 mL) was heated to 60° C. in asealed tube for 24 h. After cooling to room temperature, the reactionmixture was poured into water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulphatesulphate, filtered andconcentrated under reduce pressure. The residue was purified by flashchromatography on silica gel using a gradient of ethyl acetate (2-20%)in heptane to afford 0.153 g (14%) of the title compound as a brownsolid.

ESI/APCI(+): 224 (M+H).

Example 18 Preparation of Intermediate(2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-(p-tolyl)-methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.795 g; 5 mmol), 4-tetrahydropyranone(1.08 mL; 7.5 mmol), sulfur (0.240 g; 7.5 mmol), morpholine (0.660 mL;7.5 mmol) in ethanol (5 mL) for 20 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-50%)in heptane furnished 1.24 g (91%) of the title compound as an orangesolid.

ESI/APCI(+): 274 (M+H).

Example 19 Preparation of Intermediate(2-amino-4,7-dihydro-5H-thieno[2,3-c]-N-methyl-pyridin-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.795 g; 5 mmol), N-methyl-4-piperidone(0.872 mL; 7.5 mmol), sulfur (0.240 g; 7.5 mmol), morpholine (0.660 mL;7.5 mmol) in ethanol (5 mL) for 20 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (20-80%)in heptane furnished 1.08 g (75%) of the title compound as an orangesolid.

ESI/APCI(+): 287 (M+H).

Example 20 Preparation of Intermediate(2-amino-4,7-dihydro-5H-thieno[2,3-c]-N-benzyl-pyridin-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.795 g; 5 mmol), N-benzyl-4-piperidone(1.39 mL; 7.5 mmol), sulfur (0.240 g; 7.5 mmol), morpholine (0.660 mL;7.5 mmol) in ethanol (5 mL) for 20 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (20-80%)in heptane furnished 1.48 g (81%) of the title compound as an orangesolid.

ESI/APCI(+): 363 (M+H).

Example 21 Preparation of Intermediate(2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.795 g; 5 mmol), cycloheptanone (0.884 mL;7.5 mmol), sulfur (0.240 g; 7.5 mmol), morpholine (0.660 mL; 7.5 mmol)in ethanol (5 mL) for 24 h. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (10-30%) in heptanefurnished 0.722 g (50%) of the title compound as a yellow solid.

ESI/APCI(+): 286 (M+H).

Example 22 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-chlorophenyl)methanone

This intermediate was prepared according to the procedure A from2-chlorobenzoylacetonitrile (0.538 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.81g (93%) of the title compound as a yellow solid.

ESI/APCI(+): 292 (M+H).

Example 23 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-chlorophenyl)methanone

This intermediate was prepared according to the procedure A from3-chlorobenzoylacetonitrile (0.538 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.78g (89%) of the title compound as a yellow solid.

ESI/APCI(+): 292 (M+H).

Example 24 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone

This intermediate was prepared according to the procedure A from3,4-dichlorobenzoylacetonitrile (0.642 g; 3 mmol), cyclohexanone (0.53mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol)in ethanol (3 mL) for 24 h. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (5-30%) in heptanefurnished 0.92 g (94%) of the title compound as a yellow solid.

ESI/APCI(+): 327 (M+H).

Example 25 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-trifluoromethylphenyl)methanone

This intermediate was prepared according to the procedure A from3-(trifluoromethyl)benzoylacetonitrile (0.639 g; 3 mmol), cyclohexanone(0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5mmol) in ethanol (3 mL) for 24 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (5-30%) in heptanefurnished 0.93 g (95%) of the title compound as a yellow solid.

ESI/APCI(+): 326 (M+H).

Example 26 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-tolyl)methanone

This intermediate was prepared according to the procedure A from3-methylbenzoylacetonitrile (0.477 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.76g (93%) of the title compound as a yellow solid.

ESI/APCI(+): 272 (M+H).

Example 27 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-fluorophenyl)methanone

This intermediate was prepared according to the procedure A from4-fluorobenzoylacetonitrile (0.489 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.71g (86%) of the title compound as a yellow solid.

ESI/APCI(+): 276 (M+H).

Example 28 Preparation of Intermediate(2-amino-4-phenylthiophen-3-yl)(p-tolyl)methanone

This intermediate was prepared according to the procedure A from4-methylbenzoylacetonitrile (0.477 g; 3 mmol), acetophenone (0.526 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-60%) in heptane furnished 0.394g (45%) of the title compound as a yellow solid.

ESI/APCI(+): 294 (M+H).

Example 29 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-anisyl)methanone

This intermediate was prepared according to the procedure A from3-methoxybenzoylacetonitrile (0.525 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.767g (89%) of the title compound as a yellow solid.

ESI/APCI(+): 288 (M+H).

ESI/APCI(−): 286 (M−H).

Example 30 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dimethoxyphenyl)methanone

This intermediate was prepared according to the procedure A from3,4-dimethoxybenzoylacetonitrile (0.615 g; 3 mmol), cyclohexanone (0.53mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol)in ethanol (3 mL) for 24 h. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (5-60%) in heptanefurnished 0.913 g (96%) of the title compound as a yellow solid.

ESI/APCI(+): 318 (M+H).

Example 31 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzo[d][1,3]dioxo1-5-yl)methanone

This intermediate was prepared according to the procedure A from 33-(benzo[d][1,3]dioxo1-5-yl)-3-oxopropanenitrile (0.567 g; 3 mmol),cyclohexanone (0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol),morpholine (0.4 mL; 4.5 mmol) in ethanol (3 mL) for 24 h. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(5-60%) in heptane furnished 0.796 g (88%) of the title compound as ayellow solid.

ESI/APCI(+): 302 (M+H).

ESI/APCI(−): 300 (M−H).

Example 32 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone

This intermediate was prepared according to the procedure A from4-chlorobenzoylacetonitrile (0.359 g; 2 mmol), cyclohexanone (0.31 mL; 3mmol), sulfur (0.096 g; 3 mmol), morpholine (0.264 mL; 3 mmol) inethanol (2 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.525g (90%) of the title compound as a yellow solid.

ESI/APCI(+): 292 (M+H).

Example 33 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-ethylphenyl)methanone

This intermediate was prepared according to the procedure A from4-ethylbenzoylacetonitrile (0.346 g; 2 mmol), cyclohexanone (0.31 mL; 3mmol), sulfur (0.096 g; 3 mmol), morpholine (0.264 mL; 3 mmol) inethanol (2 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.479g (82%) of the title compound as a yellow solid.

ESI/APCI(+): 286 (M+H).

Example 34 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(pyridin-3-yl)methanone

This intermediate was prepared according to the procedure A from3-(pyridin-3-yl)-3-oxopropanenitrile (0.438 g; 3 mmol), cyclohexanone(0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5mmol) in ethanol (3 mL) for 24 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (3-100%) in heptanefurnished 0.628 g (81%) of the title compound as a yellow solid.

ESI/APCI(+): 259 (M+H).

ESI/APCI(−): 257 (M−H).

Example 35 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-trifluoromethoxyphenyl)methanone

This intermediate was prepared according to the procedure A from4-(trifluoromethoxy)benzoylacetonitrile (0.687 g; 3 mmol), cyclohexanone(0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5mmol) in ethanol (3 mL) for 24 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (5-40%) in heptanefurnished 0.818 g (80%) of the title compound as a yellow solid.

ESI/APCI(+): 342 (M+H).

ESI/APCI(−): 340 (M−H).

Example 36 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methyl-1H-indol-3-yl)methanone

This intermediate was prepared according to the procedure A from3-(2-methyl-1H-indol-3-yl)-3-oxopropanenitrile (0.594 g; 3 mmol),cyclohexanone (0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol),morpholine (0.4 mL; 4.5 mmol) in ethanol (3 mL) for 24 h. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(5-40%) in heptane furnished 0.742 g (80%) of the title compound as ayellow solid.

ESI/APCI(+): 311 (M+H).

ESI/APCI(−): 309 (M−H).

Example 37 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-fluorophenyl)methanone

This intermediate was prepared according to the procedure A from2-fluorobenzoylacetonitrile (0.489 g; 3 mmol), cyclohexanone (0.53 mL;4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5 mmol) inethanol (3 mL) for 24 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (5-60%) in heptane furnished 0.756g (92%) of the title compound as a yellow solid.

ESI/APCI(+): 276 (M+H).

ESI/APCI(−): 274 (M−H).

Example 38 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzofuran-2-yl)methanone

This intermediate was prepared according to the procedure A from3-(benzofuran-2-yl)-3-oxopropanenitrile (0.555 g; 3 mmol), cyclohexanone(0.53 mL; 4.5 mmol), sulfur (0.144 g; 4.5 mmol), morpholine (0.4 mL; 4.5mmol) in ethanol (3 mL) for 24 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (5-50%) in heptanefurnished 0.489 g (55%) of the title compound as a yellow solid.

ESI/APCI(+): 298 (M+H).

ESI/APCI(−): 296 (M−H).

Example 39 Preparation of Intermediate(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-methoxy-4-methylphenyl)methanoneStep 1:

To a solution of 3-hydroxy-4-methylbenzoic acid (4.56 g; 30 mmol) inmethanol (60 mL) was added thionyl chloride (40 drops) dropwise. Thereaction mixture was then heated to reflux for 18 hours And thevolatiles were removed under reduced pressure. The crude material waspurified by flash chromatography on silica gel using a gradient of ethylacetate (2 to 40%) in heptane to furnish 3.04 g of the methyl2-hydroxy-4-methylbenzoate (61%) as a colorless oil.

ESI/APCI(+): 167 (M−H).

Step 2:

To a solution of methyl 2-hydroxy-4-methylbenzoate (3 g; 18.2 mmol) inDMF (36 mL) was added potassium carbonate (5 g; 36.4 mmol) and methyliodide (3.35 mL; 182 mmol) dropwise. The reaction mixture was stirred atroom temperature for 24 hours. The insoluble's were filtered, washedwith ethyl acetate and the volatiles were removed under reducedpressure. The crude material was purified by flash chromatography onsilica gel using a gradient of ethyl acetate (1 to 30%) in heptane tofurnish 2.78 g of the methyl 2-methoxy-4-methylbenzoate (85%) as acolorless oil.

Step 3:

To a solution of acetonitrile (3.24 mL; 61.7 mmol) in dry THF (31 mL) at−78° C. under nitrogen atmosphere was added n-butyllithium 2.5M (15.4mL; 38.5 mmol) and the reaction mixture was stirred at −78° C. for 30minutes. Then, a solution of methyl 2-methoxy-4-methylbenzoate (2.78 g;15.4 mmol) in dry THF (18 mL) was added dropwise and the stirring wascontinued for 1.5 hour. The reaction mixture was hydrolyzed by addingHCl (1N) and the aqueous layer was extracted several times with ethylacetate. The organics were combined, dried over magnesiumsulphatesulphate and concentrated under reduced pressure. The crudematerial was purified by flash chromatography on silica gel using agradient of ethyl acetate (5 to 80%) in heptane to furnish 2.5 g of theexpected 3-(2-methoxy-4-methylphenyl)-3-oxopropanenitrile (86%) as abright yellow solid.

ESI/APCI(+): 190 (M+H).

ESI/APCI(−): 188 (M−H).

NMR (1H): 7.64 (d, J=7.95 Hz, 1H, H_(arom)), 7.05 (s, 1H, H_(arom)),6.89 (d, J=7.92 Hz, 1H, H_(arom)), 4.44 (s, 2H, CH₂), 3.89 (s, 3H,OCH₃), 2.37 (s, 3H, CH₃).

Step 4:

A mixture of 3-(3-methoxy-4-methylphenyl)-3-oxopropanenitrile (0.945 g;5 mmol), cyclohexanone (0.77 mL; 7.5 mmol), sulfur (0.240 g; 7.5 mmol)and morpholine (0.66 mL; 7.5 mmol) in dry ethanol (5 mL) was heated at60° C. in a sealed tube for 18 h. After cooling to room temperature, thereaction mixture was poured into water and extracted with ethyl acetate.The organic layer was dried over sodium sulphatesulphate, filtered andconcentrated under reduce pressure. The residue was purified by flashchromatography on silica gel using a gradient of ethyl acetate (5-100%)in heptane furnished 0.489 g (55%) of the title compound as a yellowsolid.

ESI/APCI(+): 298 (M+H).

ESI/APCI(−): 296 (M−H).

Example 40 Preparation of Intermediate(2-amino-5,7-dihydro-4H-spiro[benzo[b]thiophene-6,2′[1,3]dioxolane]-3-yl)(p-tolyl)methanone

To a solution of 3-oxo-3-p-tolylpropanenitrile (4.78 g; 30 mmol) in dryethanol (30 mL) were added 1,4-dioxaspiro[4.5]decan-8-one (7.03 g; 45mmol), morpholine (4 mL; 45 mmol) and sulfur (1.44 g; 45 mmol). Thestirred reaction mixture was heated at 60° C. for 18 hours undernitrogen atmosphere. After cooling at room temperature, ethyl acetate (5mL) was added and the precipitate was filtered, washed with a smallvolume of ethyl acetate and dried to furnish 8.5 g (86%) of the titlecompound as a bright yellow solid.

ESI/APCI(+): 330 (M+H).

Example 41 Preparation of Methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(p-tolyl)methanone(0.300 g; 1.166 mmol), methyl levunilate (0.145 mL; 1.170 mmol),chlorotrimethylsilane (0.594 mL; 4.680 mmol) in DMF (5.7 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-20%) in heptane furnished 0.260 g (64%) of the titlecompound as a yellow solid.

ESI/APCI(+): 352 (M+H); 374 (M+Na).

ESI/APCI(−): 350 (M−H).

Example 42 Preparation of Methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(phenyl)methanone(0.079 g; 0.325 mmol), methyl levunilate (0.041 mL; 0.331 mmol),chlorotrimethylsilane (0.164 mL; 1.292 mmol) in DMF (2 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-10%) in heptane furnished 0.061 g (56%) of the titlecompound as a yellow solid.

ESI/APCI(+): 338 (M+H); 360 (M+Na).

Example 43 Preparation of Methyl2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-4,5-dimethylthiophen-3-yl)(p-tolyl)methanone (0.165 g; 0.673mmol), methyl levunilate (0.083 mL; 0.670 mmol), chlorotrimethylsilane(0.340 mL; 2.679 mmol) in DMF (3.3 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-25%)in heptane furnished 0.162 g (71%) of the title compound as a yellowsolid.

ESI/APCI(+): 340 (M+H); 362 (M+Na).

ESI/APCI(−): 338 (M−H).

Example 44 Preparation of Methyl2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-5-methylthiophen-3-yl)(p-tolyl)methanone (0.300 g; 1.297 mmol),methyl levunilate (0.161 mL; 1.299 mmol), chlorotrimethylsilane (0.660mL; 5.200 mmol) in DMF (6 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-25%)in heptane furnished 0.268 g (63%) of the title compound as a yellowoil.

ESI/APCI(+): 326 (M+H); 348 (M+Na).

ESI/APCI(−): 324 (M−H).

Example 45 Preparation of Methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-4-ethyl-5-methylthiophen-3-yl)(p-tolyl)methanone (0.279 g;1.076 mmol), methyl levunilate (0.134 mL; 1.081 mmol),chlorotrimethylsilane (0.547 mL; 4.310 mmol) in DMF (5.5 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.245 g (64%) of the titlecompound as a yellow oil.

ESI/APCI(+): 354 (M+H); 376 (M+Na)

ESI/APCI(−): 352 (M−H)

Example 46 Preparation of Methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-5-ethyl-4-methylthiophen-3-yl)(p-tolyl)methanone (0.300 g;1.157 mmol), methyl levunilate (0.144 mL; 1.162 mmol),chlorotrimethylsilane (0.588 mL; 4.633 mmol) in DMF (5.5 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.273 g (67%) of the titlecompound as a yellow solid.

ESI/APCI(+): 354 (M+H); 376 (M+Na).

ESI/APCI(−): 352 (M−H).

Example 47 Preparation of Methyl2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-4-methylthiophen-3-yl)(p-tolyl)methanone (0.157 g; 0.679 mmol),methyl levunilate (0.085 mL; 0.686 mmol), chlorotrimethylsilane (0.346mL; 2.726 mmol) in DMF (3.2 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-15%)in heptane furnished 0.129 g (58%) of the title compound as a yellowsolid.

ESI/APCI(+): 326 (M+H); 348 (M+Na).

ESI/APCI(−): 324 (M−H).

Example 48 Preparation of Methyl[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-chlorophenyl)methanone(0.200 g; 0.720 mmol), methyl levunilate (0.090 mL; 0.726 mmol),chlorotrimethylsilane (0.367 mL; 2.892 mmol) in DMF (3.5 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-25%) in heptane furnished 0.150 g (56%) of the titlecompound as a yellow solid.

ESI/APCI(+): 372 (M+H).

Example 49 Preparation of Methyl2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-aminothiophen-3-yl)(p-tolyl)methanone (0.288 g; 1.325 mmol), methyllevunilate (0.165 mL; 1.331 mmol), chlorotrimethylsilane (0.677 mL;5.334 mmol) in DMF (6.2 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (10-80%)in heptane furnished 0.078 g (19%) of the title compound as a brownsolid.

ESI/APCI(+): 312 (M+H); 334 (M+Na).

Example 50 Preparation of Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone(0.400 g; 1.474 mmol), methyl levunilate (0.185 mL; 1.493 mmol),chlorotrimethylsilane (0.752 mL; 5.925 mmol) in DMF (7 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-25%) in heptane furnished 0.403 g (75%) of the titlecompound as a yellow solid.

ESI/APCI(+): 366 (M+H); 388 (M+Na).

ESI/APCI(−): 364 (M−H).

Example 51 Preparation of Methyl[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-trifluoromethylphenyl)methanone(0.296 g; 0.951 mmol), methyl levunilate (0.120 mL; 0.968 mmol),chlorotrimethylsilane (0.486 mL; 3.829 mmol) in DMF (4.5 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-25%) in heptane furnished 0.218 g (57%) of the titlecompound as a yellow solid.

ESI/APCI(+): 406 (M+H).

ESI/APCI(−): 404 (M−H).

Example 52 Preparation of Methyl[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-ethylphenyl)methanone(0.333 g; 1.227 mmol), methyl levunilate (0.155 mL; 1.251 mmol),chlorotrimethylsilane (0.627 mL; 4.940 mmol) in DMF (5.8 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-25%) in heptane furnished 0.291 g (65%) of the titlecompound as an orange oil.

ESI/APCI(+): 366 (M+H); 388 (M+Na).

ESI/APCI(−): 364 (M−H).

Example 53 Preparation of Methyl[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate

A suspension of methyl[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.225 mg; 0.616 mmol) and2,3-Dichloro-5,6-Dicyanobenzoquinone (0.351 mg; 1.546 mmol) in1,2-dichlorobenzene (2 mL) was placed in a sealed tube and wasirradiated in a microwave oven at 190° C. for 10 minutes. The reactionmixture was then evaporated to dryness under reduced pressure. Theresidue was suspended in dichloromethane and the solid was filteredthrough celite. The filtrate was concentrated under reduced pressure andthe residue was purified by flash chromatography on silica gel using agradient of ethyl acetate (10-30%) in heptane to afford 0.125 g (56%) ofthe title compound as a pink solid.

ESI/APCI(+): 362 (M+H); 384 (M+Na).

ESI/APCI(−): 360 (M−H).

Example 54 Preparation of Methyl[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-p-tolylmethanone(0.257 g; 1 mmol), methyl-3-benzoylpropionate (0.211 g; 1.1 mmol),chlorotrimethylsilane (0.526 mL; 4 mmol) in DMF (4 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.198 g (48%) of the titlecompound as a yellow oil.

ESI/APCI(+): 414 (M+H).

Example 55 Preparation of Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate

This compound was prepared according to the procedure B fromN-tert-Butyloxycarbonyl(2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone(0.744 g; 2 mmol), methyl levunilate (0.282 mL; 2.2 mmol),chlorotrimethylsilane (1.02 mL; 8 mmol) in DMF (4 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (10-100%) in dichloromethane (+0.5% triethylamine)furnished 0.101 g (13%) of the title compound as an orange oil.

ESI/APCI(+): 367 (M+H).

Example 56 Preparation of Methyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(furan-2-yl)methanone(0.440 g, 1.886 mmol), methyl levunilate (0.26 mL, 1.886 mmol),chlorotrimethylsilane (0.964 mL, 7.54 mmol) in DMF (3.7 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-50%) in heptane furnished 0.385 g (62%) of the titlecompound as a yellow solid.

ESI/APCI(+): 328 (M+H).

Example 57 Preparation of Methyl[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(thiophen-2-yl)methanone(0.510 g, 2.045 mmol), methyl levunilate (0.291 mL, 2.045 mmol),chlorotrimethylsilane (1.046 mL, 8.18 mmol) in DMF (4 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-50%) in heptane furnished 0.253 g (36%) of the titlecompound as a yellow solid.

ESI/APCI(+): 344 (M+H).

Example 58 Preparation of Methyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-methoxyphenyl)methanone(0.320 g, 1.171 mmol), methyl levunilate (0.166 mL, 1.171 mmol),chlorotrimethylsilane (0.599 mL, 4.68 mmol) in DMF (2.3 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-50%) in heptane furnished 0.230 g (53%) of the titlecompound as a yellow oil.

ESI/APCI(+): 368 (M+H).

EXAMPLE 59 Preparation of Methyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)tert-butylmethanone(0.180 g, 0.806 mmol), methyl levunilate (0.114 ml, 0.806 mmol),chlorotrimethylsilane (0.412 μl, 3.22 mmol) in DMF (1.6 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-30%) in heptane furnished 0.067 g (26%) of the titlecompound as a yellow oil.

ESI/APCI(+): 318 (M+H).

Example 60 Preparation of Methyl[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-(p-tolyl)-methanone(0.546 g; 2 mmol), methyl levunilate (0.282 mL; 2.2 mmol),chlorotrimethylsilane (1 mL; 8 mmol) in DMF (8 mL) for 22 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-80%) in heptane furnished 0.270 g (36%) of the titlecompound as a yellow solid.

ESI/APCI(+): 368 (M+H).

Example 61 Preparation of Methyl[7-methyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,7-dihydro-5H-thieno[2,3-c]-N-methyl-pyridin-3-yl)(p-tolyl)methanone(0.572 g; 2 mmol), methyl levunilate (0.282 mL; 2.2 mmol),chlorotrimethylsilane (1 mL; 8 mmol) in DMF (8 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofmethanol (1-20%) in dichloromethane furnished 0.187 g (24%) of the titlecompound as a dark yellow oil.

ESI/APCI(+): 381 (M+H).

Example 62 Preparation of Methyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,7-dihydro-5H-thieno[2,3-c]-N-benzyl-pyridin-3-yl)(p-tolyl)methanone(0.724 g; 2 mmol), methyl levunilate (0.282 mL; 2.2 mmol),chlorotrimethylsilane (1 mL; 8 mmol) in DMF (8 mL) for 22 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-90%) in heptane furnished 0.160 g (17%) of the titlecompound as a yellow oil.

ESI/APCI(+): 457 (M+H).

Example 63 Preparation of Methyl[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophen-3-yl)(p-tolyl)methanone(0.713 g; 2.5 mmol), methyl levulinate (0.350 mL; 2.75 mmol),chlorotrimethylsilane (1.27 mL; 10 mmol) in DMF (10 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-40%) in heptane furnished 0.510 g (52%) of the titlecompound as a yellow solid.

ESI/APCI(+): 390 (M+H).

Example 64 Preparation of Methyl[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-chlorophenyl)methanone(0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.302 g (78%) of the titlecompound as a yellow solid.

ESI/APCI(+): 386 (M+H).

Example 65 Preparation of Methyl[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-chlorophenyl)methanone(0.291 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.296 g (76%) of the titlecompound as a yellow solid.

ESI/APCI(+): 386 (M+H).

Example 66 Preparation of Methyl[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone(0.228 g; 0.7 mmol), methyl levulinate (0.099 mL; 0.77 mmol),chlorotrimethylsilane (0.357 mL; 2.8 mmol) in DMF (2.8 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.194 g (66%) of the titlecompound as a yellow solid.

ESI/APCI(+): 421 (M+H).

Example 67 Preparation ofMethyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-trifluoromethylphenyl)methanone(0.325 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.262 g (62%) of the titlecompound as a yellow solid.

ESI/APCI(+): 420 (M+H).

Example 68 Preparation ofMethyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-tolyl)methanone(0.271 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.320 g (87%) of the titlecompound as a yellow solid.

ESI/APCI(+): 366 (M+H).

Example 69 Preparation ofMethyl[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-fluorophenyl)methanone(0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.302 g (82%) of the titlecompound as a yellow solid.

ESI/APCI(+): 370 (M+H).

Example 70 Preparation of Methyl2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate

This compound was prepared according to the procedure B from(2-amino-4-phenylthiophen-3-yl)(p-tolyl)methanone (0.264 g; 0.9 mmol),methyl levulinate (0.127 mL; 0.99 mmol), chlorotrimethylsilane (0.460mL; 3.6 mmol) in DMF (3.6 mL) for 48 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (3-40%)in heptane furnished 0.297 g (85%) of the title compound as a yellowsolid.

ESI/APCI(+): 388 (M+H).

Example 71 Preparation ofMethyl[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(m-anisyl)methanone(0.287 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.327 g (85%) of the titlecompound as a yellow solid.

ESI/APCI(+): 382 (M+H).

Example 72 Preparation ofMethyl[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dimethoxyphenyl)methanone(0.317 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.330 g (80%) of the titlecompound as a yellow solid.

ESI/APCI(+): 412 (M+H).

Example 73 Preparation ofMethyl[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzo[d][1,3]dioxol-5-yl)methanone(0.301 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.328 g (83%) of the titlecompound as a yellow solid.

ESI/APCI(+): 396 (M+H).

Example 74 Preparation ofMethyl[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydropThenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-chlorophenyl)methanone(0.525 g; 1.8 mmol), methyl levulinate (0.254 mL; 1.98 mmol),chlorotrimethylsilane (0.922 mL; 7.2 mmol) in DMF (7.2 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.509 g (73%) of the titlecompound as a yellow solid.

ESI/APCI(+): 386 (M+H).

Example 75 Preparation ofMethyl[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-ethylphenyl)methanone(0.471 g; 1.65 mmol), methyl levulinate (0.233 mL; 1.81 mmol),chlorotrimethylsilane (0.845 mL; 6.6 mmol) in DMF (6.6 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.463 g (74%) of the titlecompound as a yellow solid.

ESI/APCI(+): 380 (M+H).

Example 76 Preparation ofMethyl[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(pyridin-3-yl)methanone(0.362 g; 1.4 mmol), methyl levulinate (0.198 mL; 1.54 mmol),chlorotrimethylsilane (0.717 mL; 5.6 mmol) in DMF (5.6 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.193 g (39%) of the titlecompound as a yellow solid.

ESI/APCI(+): 353 (M+H).

Example 77 Preparation ofMethyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(4-trifluoromethoxyphenyl)methanone(0.341 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.340 g (78%) of the titlecompound as a yellow solid.

ESI/APCI(+): 436 (M+H).

Example 78 Preparation ofMethyl[2-methyl-4-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methyl-1H-indol-3-yl)methanone (0.310 g; 1 mmol), methyl levulinate (0.141 mL;1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48h. Purification by flash chromatography on silica gel using a gradientof ethyl acetate (5-70%) in heptane furnished 0.233 g (57%) of the titlecompound as a yellow solid.

ESI/APCI(+): 405 (M+H).

Example 79 Preparation ofMethyl[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-fluorophenyl)methanone(0.275 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.320 g (86%) of the titlecompound as a yellow solid.

ESI/APCI(+): 370 (M+H).

Example 80 Preparation ofMethyl[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(benzofuran-2-yl)methanone(0.297 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol),chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.335 g (85%) of the titlecompound as a yellow solid.

ESI/APCI(+): 392 (M+H).

Example 81 Preparation ofMethyl[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(2-methoxy-4-methylphenyl)methanone(0.602 g; 2 mmol), methyl levulinate (0.282 mL; 2.2 mmol),chlorotrimethylsilane (1.02 mL; 8 mmol) in DMF (8 mL) for 48 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-50%) in heptane furnished 0.631 g (80%) of the titlecompound as a yellow solid.

ESI/APCI(+): 396 (M+H).

ESI/APCI(−): 394 (M−H).

Example 82 Preparation of Ethyl 4-oxo-2-propylpentanoate

Step 1:

In a flask equipped by a Dean-Stark trap, a mixture of ethyl levulinate(28.83 g; 200 mmol), ethylene glycol (37.24 g; 600 mmol) and a catalyticamount of pyridinium para-toluenesulfonic acid in toluene (200 mL) washeated at reflux until the theoretical amount of water was distilledoff. After cooling, the mixture was washed with a saturated solution ofsodium hydrogenocarbonate. The basic layer was extracted withdiethylether and the organics were combined, then washed with brine andwater. The organic layer was dried over sodium sulphatesulphate andconcentrated under reduced pressure to afford the ethyl3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a colorless oil.

ESI/APCI(+): 189 (M+H).

¹H NMR (CDCl₃) : δ 4.12 (q, J=7.14 and 14.25 Hz, 2H, CO₂CH₂CH₃); 3.93(m, 4H, OCH₂CH₂O); 2.37 (m, 2H, CH₂); 2.02 (m, 2H, CH₂); 1.32 (s, 3H,CH₃); 1.25 (t, J=7.14 Hz, 3H, CO₂CH₂CH₃).

Step 2:

To a cooled (−78° C.) solution of lithium diisopropylamine (30 mL; 60mmol; 2N in THF) in THF (8 mL) was added hexamethylphosphoramide (12 mL)and the solution was stirred for 30 min. A solution of ethyl3-(2-methyl-1,3-dioxolan-2-yl)propanoate (9.4 g; 50 mmol), in THF (9mL), was added over 30 min and stirring was continued for 1 h. Propyliodide (6.84 mL; 70 mmol) was slowly added and the solution was allowedto warm to room temperature for 4 h. the reaction was quenched by addinga saturated aqueous solution of ammonium chloride. The two phases wereseparated and the aqueous layer was extracted with ethyl acetate (50 mL)and the combined organic layers were dried with sodium sulphatesulphate,filtered and concentrated under reduced pressure. The crude residue waspurified by flash-chromatography on silica gel using a gradient of ethylacetate (0-40%) in heptane to furnish 9.8 g (85%) of ethyl2-((2-methyl-1,3-dioxolan-2-yl)methyl)pentanoate as an oil.

ESI/APCI(+): 231 (M+H).

Step 3:

To a solution of ethyl 2-((2-methyl-1,3-dioxolan-2-yl)methyl)pentanoate(9.8 g; 42.55 mmol) in hexane (106 mL) at −78° C. under nitrogenatmosphere was added borontribromide (55 mL; 55 mmol; 1M indichloromethane) and the reaction mixture was stirred at −20° C. for 2h. Water (50 mL) and ethyl acetate (50 mL) were added to the reactionmixture and the layers were separated. The aqueous layer was extractedwith ethyl acetate and the combined organic layers were dried oversodium sulphatesulphate, filtered and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethyl acetate (1-40%) in heptane furnished 6.41 g (81%) ofethyl 4-oxo-2-propylpentanoate as a light yellow oil.

ESI/APCI(+): 187 (M+H).

¹H NMR (CDCl₃) : δ 4.15 (q, J=7.14 and 14.25 Hz, 2H, CO₂CH₂CH₃); 2.88(m, 2H, CH₂); 2.51 (m, 1H, CH); 2.16 (s, 3H, CH₃); 1.62-1.23 (m, 7H,CH₂CH₂CH₃); 0.90 (t, J=7.14 Hz, 3H, CO₂CH₂CH₃).

Example 83 Preparation of Ethyl2-[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate

To a solution of(2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone(0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol)in dry DMF (4 mL) under nitrogen atmosphere was addedchlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture wasstirred in a sealed tube and heated at 100° C. for 24 h. An extra volumeof chlorotrimethylsilane was added (0.100 mL) and the reaction mixturewas stirred at 100° C. for 48 h. After cooling, the volatiles wereremoved under reduced pressure. Purification by flash-chromatography onsilica gel using a gradient of methanol (1-20%) in dichloromethanefurnished the title compound as a dark oil.

ESI/APCI(+): 513 (M+H).

Example 84 Preparation of Ethyl2-[2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate

To a solution of(2-amino-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone(0.286 g; 1 mmol) and ethyl 4-oxo-2-propylpentanoate (0.204 g; 1.1 mmol)in dry DMF (8 mL) under nitrogen atmosphere was addedchlorotrimethylsilane (0.511 mL; 4 mmol) dropwise. The mixture wasstirred in a sealed tube and heated at 100° C. for 24 h. An extra volumeof chlorotrimethylsilane was added (0.100 mL) and the reaction mixturewas stirred at 100° C. for 48 h. The volatiles were removed underreduced pressure and the residue was purified by flash-chromatography onsilica gel using a gradient of methanol (1-20%) in dichloromethane tofurnish the title compound as a dark oil.

ESI/APCI(+): 437 (M+H).

Example 85 Preparation of Ethyl2-[2-methyl-4-(p-tolyl)-spiro[[1,3]dioxolane-2,7]-5,6,7,8-tetrahydro-9-thia-1-aza-7-oxo-fluoren-3-yl]pentanoate

To a solution of(2-amino-5,7-dihydro-4H-spiro[benzo[b]thiophene-6,2′-[1,3]dioxolane]-3-yl)(p-tolyl)methanone(1.98 g; 6 mmol) and ethyl 4-oxo-2-propylpentanoate (1.23 g; 6.6 mmol)in dry DMF (24 mL) under nitrogen atmosphere was addedchlorotrimethylsilane (3.06 mL; 24 mmol) dropwise. The mixture wasstirred in a sealed tube and heated at 100° C. for 24 h. An extra volumeof chlorotrimethylsilane was added (0.500 mL) and the reaction mixturewas stirred at 100° C. for 48 h. After cooling, the volatiles wereremoved under reduced pressure and the residue was purified byflash-chromatography on silica gel using a gradient of ethyl acetate(10-100%) in dichloromethane to furnish 1.86 g (64%) of the titlecompound as an orange oil.

ESI/APCI(+): 437 (M+H).

Example 86 Preparation ofEthyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

This compound was prepared according to the procedure B from(2-amino-4-methylthiophen-3-yl)(p-tolyl)methanone (0.814 g; 3 mmol),ethyl levunilate (0.469 mL; 3.3 mmol), chlorotrimethylsilane (1.53 mL;12 mmol) in DMF (12 mL) for 24 h. Purification by flash chromatographyon silica gel using a gradient of ethyl acetate (1-30%) in heptanefurnished 1.02 g (89%) of the title compound as a yellow solid.

ESI/APCI(+): 380 (M+H).

Example 87 Preparation of Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C frommethyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.189 g; 0.538 mmol), LHMDS 1N in THF (0.594 mL; 0.594 mmol),1-iodopropane (0.080 mL; 0.823 mmol) in DMF (8 mL) for 4 h. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(5-15%) in heptane furnished 0.124 g (59%) of the title compound as ayellow solid.

ESI/APCI(+): 394 (M+H); 416 (M+Na).

Example 88 Preparation of Methyl2-[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C frommethyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.115 g; 0.341 mmol), LHMDS 1N in THF (0.375 mL; 0.375 mmol),1-iodopropane (0.050 mL; 0.513 mmol) in DMF (5 mL) for 3 h.

Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.111 g (86%) of the titlecompound as a yellow solid.

ESI/APCI(+): 380 (M+H); 402 (M+Na).

Example 89 Preparation of Methyl2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.113 g;0.333 mmol), LHMDS 1N in THF (0.367 mL; 0.367 mmol), 1-iodopropane(0.049 mL; 0.502 mmol) in DMF (5 mL) for 3 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-10%)in heptane furnished 0.074 g (58%) of the title compound as a yellowsolid.

ESI/APCI(+): 382 (M+H); 404 (M+Na).

ESI/APCI(−): 380 (M−H).

Example 90 Preparation of Methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate(0.200 g; 0.566 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol),1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.131 g (59%) of the titlecompound as a white solid. ESI/APCI(+): 396 (M+H); 418 (M+Na).

Example 91 Preparation of Methyl2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.188 g;0.578 mmol), LHMDS 1N in THF (0.650 mL; 0.650 mmol), 1-iodopropane(0.092 mL; 0.943 mmol) in DMF (8 mL) for 4 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-15%)in heptane furnished 0.139 g (65%) of the title compound as a yellowoil.

ESI/APCI(+): 368 (M+H); 390 (M+Na).

Example 92 Preparation of Methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate(0.196 g; 0.554 mmol), LHMDS 1N in THF (0.635 mL; 0.635 mmol),1-iodopropane (0.090 mL; 0.923 mmol) in DMF (8 mL) for 3.5 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.119 g (54%) of the titlecompound as a colorless oil.

ESI/APCI(+): 396 (M+H); 418 (M+Na).

Example 93 Preparation of Methyl2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g;0.246 mmol), LHMDS 1N in THF (0.280 mL; 0.280 mmol), 1-iodopropane(0.040 mL; 0.410 mmol) in DMF (3.5 mL) for 3.5 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-15%)in heptane furnished 0.087 g (96%) of the title compound as a whitesolid.

ESI/APCI(+): 368 (M+H); 390 (M+Na).

Example 94 Preparation of Methyl2-[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.100 g; 0.269 mmol), LHMDS 1N in THF (0.305 mL; 0.305 mmol),1-iodopropane (0.044 mL; 0.451 mmol) in DMF (3.8 mL) for 4 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.049 g (44%) of the titlecompound as a yellow solid.

ESI/APCI(+): 414 (M+H).

Example 95 Preparation of Methyl2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate

This compound was prepared according to the procedure C from methyl2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.078 g; 0.250mmol), LHMDS 1N in THF (0.276 mL; 0.276 mmol), 1-iodopropane (0.041 mL;0.420 mmol) in DMF (3.6 mL) for 4 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-15%)in heptane furnished 0.052 g (59%) of the title compound as a colorlessoil.

ESI/APCI(+): 354 (M+H); 376 (M+Na).

Example 96 Preparation of Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.120 g; 0.328 mmol), LHMDS 1N in THF (0.362 mL; 0.362 mmol),1-iodopropane (0.054 mL; 0.554 mmol) in DMF (5 mL) for 3.5 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.101 g (75%) of the titlecompound as a white solid.

ESI/APCI(+): 408 (M+H); 430 (M+Na).

ESI/APCI(−): 406 (M−H).

Example 97 Preparation of Methyl2-[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.114 g; 0.281 mmol), LHMDS 1N in THF (0.312 mL; 0.312 mmol),1-iodopropane (0.046 mL; 0.472 mmol) in DMF (4 mL) for 3.5 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.088 g (70%) of the titlecompound as a yellow solid.

ESI/APCI(+): 448 (M+H).

ESI/APCI(−): 446 (M−H).

Example 98 Preparation of Methyl2-[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)acetate(0.120 g; 0.328 mmol), LHMDS 1N in THF (0.365 mL; 0.365 mmol),1-iodopropane (0.052 mL; 0.533 mmol) in DMF (4.7 mL) for 4 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-15%) in heptane furnished 0.081 g (61%) of the titlecompound as a white solid.

ESI/APCI(+): 408 (M+H); 430 (M+Na).

ESI/APCI(−): 406 (M−H).

Example 99 Preparation of Methyl2-[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.150 g;0.415 mmol), LHMDS 1N in THF (0.462 mL; 0.462 mmol), 1-iodopropane(0.066 mL; 0.677 mmol) in DMF (6 mL) for 3 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-30%)in heptane furnished 0.126 g (75%) of the title compound as a colorlessoil.

ESI/APCI(+): 404 (M+H); 426 (M+Na).

ESI/APCI(−): 402 (M−H).

Example 100 Preparation of Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxymethylether-butanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.386 g; 1.1 mmol), LHMDS 1N in THF (1.21 mL; 1.21 mmol),1-bromo-2-(methoxymethoxy)ethane (0.193 mL; 1.65 mmol) in DMF (4 mL) for18 h. Purification by flash chromatography on silica gel using agradient of ethyl acetate (3-30%) in heptane furnished 0.361 g (75%) ofthe title compound as a colorless oil.

ESI/APCI(+): 440 (M+H); 462 (M+Na).

Example 101 Preparation of Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.386 g; 1.1 mmol), LHMDS 1N in THF (1.21 mL; 1.21 mmol),1-bromo-2-(methoxymethoxy)ethane (0.155 mL; 1.65 mmol) in DMF (4 mL) for18 h. Purification by flash chromatography on silica gel using agradient of ethyl acetate (3-30%) in heptane furnished 0.077 g (39%) ofthe title compound as a colorless oil.

ESI/APCI(+): 410 (M+H).

Example 102 Preparation of methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acrylate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.386 g; 1.1 mmol), LHMDS 1N in THF (1.21 mL; 1.21 mmol),para-formaldehyde (0.050 g; 1.65 mmol) in DMF (4 mL) for 4 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-100%) in heptane furnished 0.154 g (36%) of the titlecompound as a light yellow solid.

ESI/APCI(+): 364 (M+H).

Example 103 Preparation of methyl2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylacetate

This compound was prepared according the following procedure: To asolution of methyl[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetatein dry DMF (4 mL) at −10° C. was added sodium hydride (60% in mineraloil) (0.048 g; 1.2 mmol) and bromocyclopentane (0.120 mL; 1.5 mmol). Thereaction mixture was allowed to warm up to room temperature and stirredfor 18 h. The reaction mixture was then heated to 70° C. for 24 h. Asaturated solution of ammonium chloride (10 ml) was added and themixture was extracted with ethyl acetate. The organic layers werecombined, washed with brine, dried over magnesium sulphatesulphate andconcentrated under reduced pressure. The crude material was purified byflash-chromatography on silica gel column using a gradient of ethylacetate (3 to 30%) in heptane to furnish 0.077 g (18%) of the titlecompound as a colorless oil.

ESI/APCI(+): 420 (M+H).

Example 104 Preparation of methyl2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.351 g; 1 mmol), LHMDS 1N in THF (1.1 mL; 1.1 mmol), 1bromomethylmethylether (0.122 mL; 1.5 mmol) in DMF (4 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-30%) in heptane furnished 0.307 g (77%) of the titlecompound as a colorless oil.

ESI/APCI(+): 396 (M+H).

Example 105 Preparation of Methyl2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from Methyl[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.185 g; 0.45 mmol), LHMDS 1N in THF (0.495 mL; 0.495 mmol),1-iodopropane (0.066 mL; 0.675 mmol) in DMF (1.3 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-30%) in heptane furnished 0.194 g (95%) of the titlecompound as a yellow oil.

Example 106 Preparation of Methyl2-[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from Methyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.395 g; 1.206 mmol), LHMDS 1N in THF (1.327 mL; 1.327 mmol),1-iodopropane (0.177 mL; 1.810 mmol) in DMF (4.8 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-40%) in heptane furnished 0.335 g (75%) of the titlecompound as a yellow oil.

ESI/APCI(+): 370 (M+H).

Example 107 Preparation of Methyl2-[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from Methyl[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.261 g; 0.760 mmol), LHMDS 1N in THF (0.836 mL; 0.836 mmol),1-iodopropane (0.111 mL; 1.140 mmol) in DMF (3.0 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-40%) in heptane furnished 0.249 g (85%) of the titlecompound as a yellow oil.

ESI/APCI(+): 386 (M+H).

Example 108 Preparation of Methyl2-[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from Methyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.245 g; 0.667 mmol), LHMDS 1N in THF (0.733 mL; 0.733 mmol),1-iodopropane (0.098 mL; 1.000 mmol) in DMF (2.6 mL) for 18 h.

Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-40%) in heptane furnished 0.100 g (37%) of the titlecompound as a yellow oil.

ESI/APCI(+): 410 (M+H).

Example 109 Preparation of Methyl2-[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from Methyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.067 g; 0.211 mmol), LHMDS 1N in THF (0.232 mL; 0.232 mmol),1-iodopropane (0.031 mL; 0.317 mmol) in DMF (0.85 mL) for 3 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-20%) in heptane furnished 0.035 g (46%) of the titlecompound as a yellow oil.

ESI/APCI(+): 360 (M+H).

Example 110 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate(0.270 g; 0.73 mmol), LHMDS 1N in THF (0.8 mL; 0.8 mmol), 1-iodopropane(0.122 mL; 1.09 mmol) in DMF (3 mL) for 19 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-40%)in heptane furnished 0.089 g (30%) of the title compound as a yellowoil.

ESI/APCI(+): 410 (M+H).

Example 111 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-benzyloxypropanoate

To a solution of methyl[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.175 g; 0.5 mmol) in dry DMF (2 mL) at -10° C. was added LHMDS 1N inTHF (0.55 mL; 0.55 mmol), chloromethylbenzylether (0.138 mL; 1 mmol) andpotassium iodide (0.166 g; 1 mmol). The reaction mixture was allowed towarm up to room temperature and stirred for 19 h. A saturated solutionof ammonium chloride (4 ml) was added and the mixture was extracted withethyl acetate. The organic layers were combined, washed with brine,dried over magnesium sulphatesulphate and concentrated under reducedpressure. The crude material was purified by flash-chromatography onsilica gel using a gradient of ethyl acetate (5 to 40%) in heptane tofurnish 0.057 g (24%) of the title compound as a colorless oil.

ESI/APCI(+): 472 (M+H).

Example 112 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoate

To a solution of methyl[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.175 g; 0.5 mmol) in dry DMF (2 mL) at -10° C. was added LHMDS 1N inTHF (0.55 mL; 0.55 mmol), benzylbromide (0.122 mL; 1 mmol) and potassiumiodide (0.166 g; 1 mmol). The reaction mixture was allowed to warm up toroom temperature and stirred for 19 h. A saturated solution of ammoniumchloride (4 ml) was added and the mixture was extracted with ethylacetate. The organic layers were combined, washed with brine, dried overmagnesium sulphatesulphate and concentrated under reduced pressure. Thecrude material was purified by flash-chromatography on silica gel usinga gradient of ethyl acetate (5 to 40%) in heptane to furnish 0.159 g(72%) of the title compound as a colorless oil.

ESI/APCI(+): 442 (M+H).

Example 113 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate(0.510 g; 1.3 mmol), LHMDS 1N in THF (1.44 mL; 1.44 mmol), 1-iodopropane(0.215 mL; 1.95 mmol) in DMF (4 mL) for 5 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (2-30%)in heptane furnished 0.434 g (79%) of the title compound as a yellowsolid.

ESI/APCI(+): 422 (M+H).

Example 114 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol), 1-iodo-2-methylpropane(0.115 mL; 1 mmol) in DMF (4 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-40%)in heptane furnished 0.140 g (66%) of the title compound as a yellowsolid.

ESI/APCI(+): 422 (M+H).

Example 115 Preparation of Methyl2-[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.300 g; 0.78 mmol), LHMDS 1N in THF (0.86 mL; 0.86 mmol),1-iodopropane (0.114 mL; 1.17 mmol) in DMF (3.1 mL) for 4 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-30%) in heptane furnished 0.244 g (74%) of the titlecompound as a yellow oil.

ESI/APCI(+): 428 (M+H).

Example 116 Preparation of Methyl2-[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.290 g; 0.76 mmol), LHMDS 1N in THF (0.84 mL; 0.84 mmol),1-iodopropane (0.111 mL; 1.14 mmol) in DMF (3 mL) for 18 h. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(2-30%) in heptane furnished 0.281 g (88%) of the title compound as ayellow oil.

ESI/APCI(+): 428 (M+H).

Example 117 Preparation of Methyl2-[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.190 g; 0.46 mmol), LHMDS 1N in THF (0.5 mL; 0.5 mmol), 1-iodopropane(0.067 mL; 0.69 mmol) in DMF (1.8 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (2-30%)in heptane furnished 0.172 g (82%) of the title compound as a yellowoil.

ESI/APCI(+): 463 (M+H).

Example 118 Preparation of Methyl2-[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.260 g; 0.62 mmol), LHMDS 1N in THF (0.7 mL; 0.7 mmol), 1-iodopropane(0.127 mL; 1.3 mmol) in DMF (2.5 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (2-30%)in heptane furnished 0.233 g (83%) of the title compound as a yellowoil.

ESI/APCI(+): 462 (M+H).

Example 119 Preparation of Methyl2-[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.310 g; 0.87 mmol), LHMDS 1N in THF (0.96 mL; 0.96 mmol),1-iodopropane (0.13 mL; 1.5 mmol) in DMF (3.5 mL) for 18 h. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(2-30%) in heptane furnished 0.257 g (73%) of the title compound as ayellow oil.

ESI/APCI(+): 408 (M+H).

Example 120 Preparation of Methyl2-[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.300 g; 0.82 mmol), LHMDS 1Nin THF (0.9 mL; 0.9 mmol), 1-iodopropane (0.12 mL; 1.23 mmol) in DMF(3.3 mL) for 18 h. Purification by flash chromatography on silica gelusing a gradient of ethyl acetate (2-30%) in heptane furnished 0.290 g(85%) of the title compound as a yellow oil.

ESI/APCI(+): 412 (M+H).

Example 121 Preparation of Methyl2-[2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)]pentanoate

This compound was prepared according to the procedure C from methyl2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.297g; 0.76 mmol), LHMDS 1N in THF (1.14 mL; 1.14 mmol), 1-iodopropane(0.148 mL; 1.52 mmol) in DMF (3.8 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (3-30%)in heptane furnished 0.270 g (83%) of the title compound as a yellowoil. ESI/APCI(+): 430 (M+H).

Example 122 Preparation of Methyl2-[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.327 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol),1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-30%) in heptane furnished 0.213 g (59%) of the titlecompound as a yellow oil.

ESI/APCI(+): 424 (M+H).

Example 123 Preparation of Methyl2-[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.330 g; 0.8 mmol), LHMDS 1N in THF (1.2 mL; 1.2 mmol), 1-iodopropane(0.156 mL; 1.6 mmol) in DMF (4 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (3-80%)in heptane furnished 0.226 g (62%) of the title compound as a yellowoil.

ESI/APCI(+): 454 (M+H).

Example 124 Preparation of Methyl2-[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.328 g; 0.83 mmol), LHMDS 1N in THF (1.24 mL; 1.24 mmol),1-iodopropane (0.162 mL; 1.66 mmol) in DMF (4.1 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-40%) in heptane furnished 0.300 g (83%) of the titlecompound as a yellow oil.

ESI/APCI(+): 438 (M+H).

Example 125 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol),3-iodo-1,1,1-trifluorobutane (0.127 mL; 1 mmol) in DMF (2.5 mL) for 18h. Purification by flash chromatography on silica gel using a gradientof ethyl acetate (3-30%) in heptane furnished 0.172 g (72%) of the titlecompound as a yellow oil.

ESI/APCI(+): 476 (M+H).

Example 126 Preparation of Methyl2-[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.254 g; 0.66 mmol), LHMDS 1N in THF (0.727 mL; 0.727 mmol),1-iodopropane (0.097 mL; 0.99 mmol) in DMF (2.6 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-30%) in heptane furnished 0.196 g (69%) of the titlecompound as a yellow oil.

ESI/APCI(+): 428 (M+H).

Example 127 Preparation of Methyl2-[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.231 g; 0.61 mmol), LHMDS 1N in THF (0.67 mL; 0.67 mmol),1-iodopropane (0.089 mL; 0.913 mmol) in DMF (2.4 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-30%) in heptane furnished 0.197 g (77%) of the titlecompound as a yellow oil.

ESI/APCI(+): 422 (M+H).

Example 128 Preparation of Methyl2-[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.096 g; 0.27 mmol), LHMDS 1N in THF (0.3 mL; 0.3 mmol), 1-iodopropane(0.039 mL; 0.4 mmol) in DMF (1.1 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (3-30%)in heptane furnished 0.197 g (77%) of the title compound as a yellowoil.

ESI/APCI(+): 395 (M+H).

Example 129 Preparation of Methyl2-[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.340 g; 0.78 mmol), LHMDS 1N in THF (1.17 mL; 1.17 mmol),1-iodopropane (0.152 mL; 1.56 mmol) in DMF (3.9 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-40%) in heptane furnished 0.271 g (73%) of the titlecompound as a yellow oil.

ESI/APCI(+): 478 (M+H).

Example 130 Preparation of Methyl2-[2-methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.233 g; 0.57 mmol), LHMDS 1N in THF (0.85 mL; 0.85 mmol),1-iodopropane (0.111 mL; 1.14 mmol) in DMF (2.8 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-50%) in heptane furnished 0.129 g (50%) of the titlecompound as a yellow oil.

ESI/APCI(+): 488 (M+H).

Example 131 Preparation of Methyl2-[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.320 g; 0.86 mmol), LHMDS 1N in THF (1.29 mL; 1.29 mmol),1-iodopropane (0.168 mL; 1.72 mmol) in DMF (4.3 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (2-40%) in heptane furnished 0.266 g (75%) of the titlecompound as a yellow oil.

ESI/APCI(+): 412 (M+H).

Example 132 Preparation of Methyl2-[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.335 g; 0.85 mmol), LHMDS 1N in THF (1.27 mL; 1.27 mmol),1-iodopropane (0.166 mL; 1.7 mmol) in DMF (4.2 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (3-40%) in heptane furnished 0.302 g (82%) of the titlecompound as a yellow oil.

ESI/APCI(+): 434 (M+H).

Example 133 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5, 6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF(0.75 mL; 0.75 mmol), (2-bromoethyl)benzene (0.136 mL; 1 mmol) in DMF(2.5 mL) for 18 h. Purification by flash chromatography on silica gelusing a gradient of ethyl acetate (3-30%) in heptane furnished 0.128 g(55%) of the title compound as a yellow oil.

ESI/APCI(+): 470 (M+H).

Example 134 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5, 6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF(0.75 mL; 0.75 mmol), 2-iodopropane (0.100 mL; 1 mmol) in DMF (2.5 mL)for 18 h. Purification by flash chromatography on silica gel using agradient of ethyl acetate (3-30%) in heptane furnished 0.109 g (54%) ofthe title compound as a yellow oil.

ESI/APCI(+): 408 (M+H).

Example 135 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodobutane (0.115 mL; 1mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (3-30%) in heptanefurnished 0.108 g (51%) of the title compound as a yellow oil.

ESI/APCI(+): 421 (M+H).

Example 136 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF(0.75 mL; 0.75 mmol), 1,1,1-trifluoro-3-iodopropane (0.117 mL; 1 mmol)in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silicagel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.061g (25%) of the title compound as a yellow oil.

ESI/APCI(+): 462 (M+H).

Example 137 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yn-oate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), propargylbromide (0.111 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification byflash chromatography on silica gel using a gradient of ethyl acetate(3-30%) in heptane furnished 0.061 g (25%) of the title compound as ayellow oil.

ESI/APCI(+): 404 (M+H).

Example 138 Preparation of Methyl2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-42-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.395 g; 1 mmol), LHMDS 1N in THF (1.1 mL; 1.1 mmol), 1-iodopropane(0.146 mL; 1.5 mmol) in DMF (4 mL) for 18 h. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-100%)in heptane furnished 0.390 g (89%) of the title compound as a yellowoil.

ESI/APCI(+): 438 (M+H).

Example 139 Preparation of Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate

This compound was prepared according to the procedure C from methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.183 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol),1-iodo-2,2-dimethylpropane (0.100 mL; 0.75 mmol) in DMF (2 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.043 g (20%) of the titlecompound as a yellow solid.

ESI/APCI(+): 436 (M+H).

Example 140 Preparation of Ethyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate

This compound was prepared according to the procedure C from ethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.190 g; 0.5 mmol), LHMDS 1N in THF (0.55 mL; 0.55 mmol),bromomethylcyclopropane (0.096 mL; 1 mmol) in DMF (2 mL) for 18 h.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (1-30%) in heptane furnished 0.036 g (16%) of the titlecompound as a colorless oil.

ESI/APCI(+): 434 (M+H).

Example 141 Preparation of2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.100 g; 0.254 mmol) in a mixture of dioxane (5 mL) and water (1.3 mL)was added a 1N lithium hydroxide solution (2.55 mL; 2.55 mmol). Thereaction mixture was heated at 60° C. for 8 h. After cooling to roomtemperature, the reaction mixture was acidified with 1N HCl (pH-2) andpartially concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphatesulphate, filtered andconcentrated under reduced pressure. The residue was crystallized from amixture of ethyl acetate/heptane to afford 0.039 g (40%) of the titlecompound as a white solid.

ESI/APCI(+): 380 (M+H); 402 (M+Na).

ESI/APCI(−): 378 (M−H).

¹H NMR (DMSO-d₆) δ 12.47 (1H, s); 7.30 (2H, d); 7.12 (2H, d); 3.67 (1H,m); 2.89 (2H, m); 2.51 (3H, s); 2.40 (3H, s); 2.13 (2H, m); 1.99 (2H,m); 1.77 (1H, m); 1.54 (1H, m); 0.8-1.1 (2H, m); 0.66 (3H, t, J=7.1 Hz).

Example 142 Preparation of[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid

To a solution of methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.071 g; 0.202 mmol) in dioxane (4 mL) and water (1 mL) was added a 1Nlithium oxide solution (1 mL; 1 mmol). The reaction mixture was heatedat 60° C. for 2 h. After cooling to room temperature, the reactionmixture was acidified with 1N HCl (pH-2) and partially concentratedunder reduced pressure. The residue was partitioned between ethylacetate and water. The organic layer was washed with brine, dried oversodium sulphatesulphate, filtered and concentrated under reducedpressure. The residue was crystallized from a mixture of ethylacetate/heptane to afford 0.043 g (63%) of the title compound as a beigepowder.

ESI/APCI(+): 338 (M+H); 360 (M+Na).

ESI/APCI(−): 336 (M−H).

¹H NMR (DMSO-d₆) δ 12.43 (1H, brs); 7.29 (2H, d); 7.09 (2H, d); 3.46(2H, s); 2.90 (2H, m); 2.54 (3H, s); 2.40 (3H, s); 2.11 (2H, m); 1.95(2H, m).

Example 143 Preparation of[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid

To a solution of methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate(0.061 g; 0.181 mmol) in dioxane (4 mL) and water (1 mL) was added a 1Nlithium oxide solution (1 mL; 1 mmol). The reaction mixture was heatedat 65° C. for 2.5 h. After cooling to room temperature, the reactionmixture was acidified with 1N HCl (pH-2) and partially concentratedunder reduced pressure. The residue was partitioned between ethylacetate and water. The organic layer was washed with brine, dried oversodium sulphatesulphate, filtered and concentrated under reducedpressure. The residue was crystallized from a mixture of ethylacetate/heptane to afford 0.031 g (54%) of the title compound as a beigepowder.

ESI/APCI(+): 324 (M+H).

ESI/APCI(−): 322 (M−H).

¹H NMR (DMSO-d₆) δ 12.44 (1H, brs); 7.49 (3H, m); 7.21 (2H, m); 3.47(2H, s); 2.90 (2H, m); 2.55 (3H, s); 2.15 (2H, m); 1.91 (2H, m).

Example 144 Preparation of2-(2,3,6-Trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid

To a solution of methyl2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.049 g;0.144 mmol) in dioxane (3.5 mL) and water (0.9 mL) was added a 1Nlithium oxide solution (0.9 mL; 0.90 mmol). The reaction mixture washeated at 60° C. for 2 h. After cooling to room temperature, thereaction mixture was acidified with 1N HCl (pH-2) and partiallyconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.017 g (37%) of the title compound as a white powder.

ESI/APCI(+): 326 (M+H).

ESI/APCI(−): 324 (M−H).

¹H NMR (DMSO-d₆) δ 12.33 (1H, brs); 7.29 (2H, d); 7.06 (2H, d); 3.37(2H, s); 2.51 (3H, s); 2.40 (3H, s); 2.36 (3H, s); 1.43 (3H, s).

Example 145 Preparation of(3-Ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid

To a solution of methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate(0.045 g; 0.127 mmol) in dioxane (3 mL) and water (0.8 mL) was added a1N lithium oxide solution (0.8 mL; 0.80 mmol). The reaction mixture washeated at 60° C. for 2 h. After cooling to room temperature, thereaction mixture was acidified with 1N HCl (pH-2) and partiallyconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.028 g (65%) of the title compound as a beige solid.

ESI/APCI(+): 340 (M+H); 362 (M+Na).

ESI/APCI(−): 338 (M−H).

Example 146 Preparation of(2-Ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid

To a solution of methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate(0.077 g; 0.218 mmol) in dioxane (5 mL) and water (1.4 mL) was added a1N lithium oxide solution (1.4 mL; 1.40 mmol). The reaction mixture washeated at 65° C. for 2 h. After cooling to room temperature, thereaction mixture was acidified with 1N HCl (pH-2) and partiallyconcentrated under reduced pressure. The residue was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.043 g (58%) of the title compound as a white powder.

ESI/APCI(+): 340 (M+H); 362 (M+Na).

ESI/APCI(−): 338 (M−H).

Example 147 Preparation of(2,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetic acid

To a solution of methyl2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.080 g;0.246 mmol) in dioxane (4 mL) and water (1.5 mL) was added a 1N lithiumoxide solution (1.5 mL; 1.50 mmol). The reaction mixture was heated at60° C. for 4 h. After cooling to room temperature, the reaction mixturewas acidified with 1N HCl (pH-2) and partially concentrated underreduced pressure. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with brine, dried over sodiumsulphate, filtered and concentrated under reduced pressure. The residuewas crystallized from a mixture of ethyl acetate/heptane to afford 0.037g (48%) of the title compound as a beige solid.

ESI/APCI(+): 312 (M+H); 334 (M+Na).

ESI/APCI(−): 310 (M−H).

Example 148 Preparation of2-[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.111 g; 0.292 mmol) in dioxane (4 mL) and water (1 mL) was added a 1Nlithium oxide solution (1.8 mL; 1.80 mmol). The reaction mixture washeated at 60° C. for 3 h and 1N lithium oxide solution (0.9 mL; 0.90mmol) was added again. After 2.5 h at 60° C., the reaction mixture wasacidified with 1N HCl (pH-2) and partially concentrated under reducedpressure. The residue was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over sodium sulphate,filtered and concentrated under reduced pressure. The residue wascrystallized from a mixture of ethyl acetate/heptane to afford 0.051 g(48%) of the title compound as a white powder.

ESI/APCI(+): 366 (M+H); 388 (M+Na).

ESI/APCI(−): 364 (M−H).

¹H NMR (DMSO-d6) δ 12.49 (1H, brs); 7.49 (3H, m); 7.26 (2H, m); 3.65(1H, m); 2.89 (2H, m); 2.53 (3H, s); 2.13 (2H, m); 1.98 (2H, m); 1.75(1H, m); 1.53 (1H, m); 0.8-1.1 (2H, m); 0.64 (3H, t, J=7.2 Hz).

Example 149 Preparation of2-(2,3,6-Trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid

To a solution of methyl2-(2,3,6-trimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.074g; 0.194 mmol) in methanol (4 mL) and ethanol (2 mL) was added a 5%sodium hydroxide solution (2 mL; 2.50 mmol). The reaction mixture washeated under reflux for 2 h. 5% sodium hydroxide solution (2 mL; 2.500mmol) was added again and reflux was maintained for 2 h. 5% Sodiumhydroxide solution (1 mL; 1.250 mmol) was added. After 3 h at reflux,the reaction mixture was concentrated under reduced pressure. Theresidue was suspended in water, acidified with 1N HCl (pH-2) andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over sodium sulphate, filtered and concentrated underreduced pressure. The residue was crystallized from a mixture of ethylacetate/heptane to afford 0.037 g (52%) of the title compound as a whitepowder.

ESI/APCI(+): 368 (M+H).

ESI/APCI(−): 366 (M−H).

¹H NMR (DMSO-d₆) δ 12.42 (1H, s); 7.31 (2H, d); 7.12 (2H, d); 3.55 (1H,m); 2.50 (3H, s); 2.41 (3H, s); 2.35 (3H, s); 1.99 (1H, m); 1.50 (1H,m); 1.39 (3H, s); 1.08 (1 H, m); 0.89 (1 H, m); 0.67 (3H, t, J=7.2 Hz).

Example 150 Preparation of2-(3-Ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid

To a solution of methyl2-(3-ethyl-2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate(0.130 g; 0.329 mmol) in methanol (7 mL) and ethanol (3.5 mL) was addeda 5% sodium hydroxide solution (9 mL; 11.25 mmol). The reaction mixturewas heated under reflux for 5 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas suspended in water, acidified with 1N HCl (pH-2) and extracted withethyl acetate. The organic layer was washed with water and brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.068 g (54%) of the title compound as a white powder.

ESI/APCI(+): 382 (M+H); 404 (M+Na).

ESI/APCI(−): 380 (M−H).

¹H NMR (DMSO-d₆) δ 12.42 (1H, brs); 7.31 (2H, m); 7.16 (2H, m); 3.49(1H, m); 2.50 (3H, s); 2.41 (3H, 5); 2.38 (3H, s); 2.00 (1H, m); 1.86(1.48 (1H, m); 1.10 (1H, m); 0.90 (1H, m); 0.58-0.69 (6H, m).

Example 151 Preparation of2-(2,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid

To a solution of methyl2-(2,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.135 g;0.367 mmol) in methanol (8 mL) and ethanol (4 mL) was added a 5% sodiumhydroxide solution (10.5 mL; 13.125 mmol). The reaction mixture washeated under reflux for 4.5 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas suspended in water, acidified with 1N HCl (pH-2) and extracted withethyl acetate. The organic layer was washed with water and brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.107 g (82%) of the title compound as a white powder.

ESI/APCI(+): 354 (M+H).

ESI/APCI(−): 352 (M−H).

¹H NMR (DMSO-d₆) δ 12.56 (1H, brs); 7.35 (2H, m); 7.19 (2H, m); 6.42(1H, s); 3.75 (1H, m); 2.50 (3H, s); 2.47 (3H, s); 2.40 (3H, s); 1.98(1H, 1.53 (1H, m); 0.92 (2H, m); 0.62 (3H, t, J=7.3 Hz).

Example 152 Preparation of2-(2-Ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid

To a solution of methyl2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate(0.119 g; 0.301 mmol) in methanol (6.4 mL) and ethanol (3.2 mL) wasadded a 5% sodium hydroxide solution (8.2 mL; 10.25 mmol). The reactionmixture was heated under reflux for 5.5 h. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was suspended in water, acidified with 1N HCl(pH-2) and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulphate, filtered andconcentrated under reduced pressure. The residue was crystallized from amixture of ethyl acetate/heptane to afford 0.059 g (51%) of the titlecompound as a white powder.

ESI/APCI(+): 382 (M+H); 404 (M+Na).

ESI/APCI(−): 380 (M−H).

¹H NMR (DMSO-d₆) δ 12.42 (1H, brs); 7.31 (2H, m); 7.14 (2H, m); 3.55(1H, m); 2.78 (2H, q); 2.50 (3H, s); 2.40 (3H, s); 2.00 (1H, m); 1.49(1H, m); 1.41 (3H, s); 1.17 (3H, t, J=7.4 Hz); 1.08 (1H, m); 0.91 (1H,m); 0.67 (3H, t, J=7.2 Hz).

Example 153 Preparation of2-[2-Methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.049 g; 0.118 mmol) in methanol (2.5mL) and ethanol (2.6 mL) was added a 5% sodium hydroxide solution (3.3mL; 4.125 mmol). The reaction mixture was heated under reflux for 4.5 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was suspended in water, acidifiedwith 1N HCl (pH-2) and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over sodium sulphate, filteredand concentrated under reduced pressure. The residue was crystallizedfrom a mixture of ethyl acetate/heptane to afford 0.029 g (61%) of thetitle compound as a white powder.

ESI/APCI(+): 400 (M+H).

ESI/APCI(−): 398 (M−H).

¹H NMR (DMSO-d₆) δ 12.55 (1H, brs); 7.57 (2H, m); 7.27 (2H, t); 3.34(1H, m); 2.90 (2H, m); 2.51 (3H, s); 2.16 (2H, m); 1.99 (2H, m); 1.81(1H, m); 1.52 (1H, m); 0.8-1.1 (2H, m); 0.64 (3H, t, J=7.2 Hz).

Example 154 Preparation of2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.100 g; 0.245 mmol) in methanol (5 mL) and ethanol (2.5 mL) was addeda 5% sodium hydroxide solution (6.6 mL; 8.250 mmol). The reactionmixture was heated under reflux for 4 h. After cooling to roomtemperature, the reaction mixture was concentrated under reducedpressure. The residue was suspended in water, acidified with 1N HCl(pH-2) and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over sodium sulphate, filtered andconcentrated under reduced pressure. The residue was crystallized from amixture of ethyl acetate/heptane to afford 0.054 g (56%) of the titlecompound as a white powder.

ESI/APCI(+): 394 (M+H).

ESI/APCI(−): 392 (M−H).

¹H NMR (DMSO-d6) δ 12.43 (1H, brs); 7.28 (2H, m); 7.13 (2H, m); 3.54(1H, m); 2.76 (2H, m); 2.50 (3H, s); 2.40 (3H, s); 1.99 (1H, m); 1.68(4H, m); 1.47 (3H, m); 1.06 (1H, m); 0.90 (1H, m); 0.66 (3H, t, J=7.1Hz).

Example 155 Preparation of(2S)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid and Example 156 Preparation of(2R)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

Step 1:

To a mixture of[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid (0.700 g; 1.78 mmol), dimethlylaminopyridine (0.112 g; 0.917 mmol),dicyclohexylcarbodiimide (0.406 g; 1.968 mmol) and 10-camphorsulfonicacid (0.042 g; 0.181 mmol) in dichloromethane (15 mL) was addedL-menthol (0.698 g; 4.467 mmol) and the reaction was stirred at roomtemperature for 90 h. The suspension was filtered and the filtratewashed with a saturated solution of aqueous sodium hydrogencarbonate,water and brine. The organic layer was dried over sodium sulphate,filtered and concentrated under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of ethyl acetate(5-80%) in heptane, followed by a second purification on silica gelusing a gradient of dichloromethane (20-100%) in heptane furnished twopure fractions A (0.115 g, 12%), B (0.140 g, 15%) and a mixture of A andB (0.407 g, 43%).

Step 2A:

To a solution of the fraction A (0.054 g; 0.102 mmol) in acetic acid(0.880 mL) in a sealed tube was added sulfuric acid (0.054 mL; 1.01mmol) and the mixture was heated at 130° C. for 3 h15. The mixture wasallowed to cool to room temperature and poured into ice. The product wasextracted with ethyl acetate and the combined organic layers were washedwith water and brine, dried over sodium sulphate, filtered andevaporated under reduced pressure. Purification by flash-chromatographyon silica using a gradient of methanol (0-20%) in dichloromethane led toa brown oil which was further purified by preparative HPLC (HPLCmethod 1) to provide 0.024 g (60%) of(2S)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid as a white solid (ee: 96%). The enantiomeric excess (ee) wasdetermined using the HPLC method 4.

ESI/APCI (+): 394 (M+H).

Step 2B:

To a solution of the fraction B (0.050 g; 0.094 mmol) in acetic acid (1mL) in a sealed tube was added sulfuric acid (0.050 mL; 0.938 mmol) andthe mixture was heated at 130° C. for 3 h15. The mixture was allowed tocool to room temperature and poured into ice. The product was extractedwith ethyl acetate and the combined organic layers were washed withwater and brine, dried over sodium sulphate, filtered and evaporatedunder reduced pressure. Purification by flash-chromatography on silicausing a gradient of methanol (0-20%) in dichloromethane led to a brownoil which slowly solidified. The product was dissolved in a minimalamount of acetonitrile and water was added to precipitate the product.The solution was kept at 4° C. for 3 days. The solid was filtered,washed with water and dried under reduced pressure to furnish 0.037 g(100%) of(2R)42-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid as a white solid. (ee: 92%). The enantiomeric excess (ee) wasdetermined using the HPLC method 4.

ESI/APCI (+): 394 (M+H).

Example 157 Preparation of2-[2-Methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.087 g; 0.194 mmol) inmethanol (4 mL) and ethanol (2 mL) was added a 5% sodium hydroxidesolution (5.2 mL; 6.500 mmol). The reaction mixture was heated underreflux for 5 h. After cooling to room temperature, the reaction mixturewas concentrated under reduced pressure. The residue was suspended inwater, acidified with 1N HCl (pH-2) and extracted with ethyl acetate.The organic layer was washed with water and brine, dried over sodiumsulphate, filtered and concentrated under reduced pressure. The residuewas crystallized from a mixture of ethyl acetate/heptane to afford 0.039g (46%) of the title compound as a white powder.

ESI/APCI(+): 434 (M+H).

ESI/APCI(−): 432 (M−H).

¹H NMR (DMSO-d₆) δ 12.61 (1H, brs); 7.89 (2H, m); 7.48 (2H, m); 3.55(1H, m); 2.90 (2H, m); 2.55 (3H, s); 2.14 (2H, m); 1.96 (2H, m); 1.71(1H, m); 1.54 (1H, m); 0.8-1.1 (2H, m); 0.65 (3H, t, J=7.2 Hz).

Example 158 Preparation of2-[2-Methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.081 g; 0.199 mmol) in methanol (4 mL)and ethanol (2 mL) was added a 5% sodium hydroxide solution (5.3 mL;6.625 mmol). The reaction mixture was heated under reflux for 4.5 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure. The residue was suspended in water, acidifiedwith 1N HCl (pH-2) and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over sodium sulphate, filteredand concentrated under reduced pressure. The residue was crystallizedfrom a mixture of ethyl acetate/heptane to afford 0.038 g (50%) of thetitle compound as a white powder.

ESI/APCI(+): 394 (M+H).

ESI/APCI(−): 392 (M−H).

¹H NMR (DMSO-d6) δ 12.50 (1H, brs); 7.33 (2H, m); 7.15 (2H, m); 3.67(1H, m); 2.88 (2H, m); 2.74 (4H, q); 2.51 (3H, s); 2.12 (2H, m); 1.99(2H, m); 1.75 (1H, m); 1.54 (1H, m); 1.24 (3H, t, J=7.2 Hz); 0.8-1.1(2H, m); 0.64 (3H, t, J=7.0 Hz).

Example 159 Preparation of2-(3,6-Dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid

To a solution of methyl2-(3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.087 g;0.237 mmol) in methanol (5 mL) and ethanol (2.6 mL) was added a 5%sodium hydroxide solution (6.8 mL; 8.500 mmol). The reaction mixture washeated under reflux for 5 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas suspended in water, acidified with 1N HCl (pH-2) and extracted withethyl acetate. The organic layer was washed with water and brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.052 g (62%) of the title compound as a white solid.

ESI/APCI(+): 354 (M+H).

ESI/APCI(−): 352 (M−H).

¹H NMR (DMSO-d6) δ 12.48 (1H, brs); 7.31 (3H, m); 7.15 (2H, t); 3.59(1H, m); 2.51 (3H, s); 2.40 (3H, s); 2.02 (1H, m); 1.53 (4H, s); 1.07(1H, m); 0.92 (1 H, m); 0.68 (3H, t, J=7.3 Hz).

Example 160 Preparation of2-(6-Methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoic acid

To a solution of methyl2-(6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.051 g;0.144 mmol) in methanol (3 mL) and ethanol (1.5 mL) was added a 5%sodium hydroxide solution (3.9 mL; 4.875 mmol). The reaction mixture washeated under reflux for 4 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas suspended in water, acidified with 1N HCl (pH-2) and extracted withethyl acetate. The organic layer was washed with water and brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.027 g (55%) of the title compound as a white solid.

ESI/APCI(+): 340 (M+H); 362 (M+Na).

ESI/APCI(−): 338 (M−H).

¹H NMR (DMSO-d₆) δ 5 12.60 (1H, brs); 7.66 (1H, d, J=5.8 Hz); 7.37 (2H,m); 7.22 (2H, m); 6.71 (1H, d, J=5.8 Hz); 3.79 (1H, m); 2.50 (3H, s);2.41 (3H, s); 1.99 (1H, m); 1.54 (1H, m); 0.94 (2H, m); 0.62 (3H, t,J=7.1 Hz). Example 161 Preparation of2-p-Methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoic acid

To a solution of methyl[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.122g; 0.302 mmol) in methanol (6.2 mL) and ethanol (3.1 mL) was added a 5%sodium hydroxide solution (8 mL; 10.00 mmol). The reaction mixture washeated under reflux for 3 h. After cooling to room temperature, thereaction mixture was concentrated under reduced pressure. The residuewas suspended in water, acidified with 1N HCl (pH-2) and extracted withethyl acetate. The organic layer was washed with water and brine, driedover sodium sulphate, filtered and concentrated under reduced pressure.The residue was crystallized from a mixture of ethyl acetate/heptane toafford 0.031 g (26%) of the title compound as a white solid.

ESI/APCI(+): 390 (M+H); 412 (M+Na).

ESI/APCI(−): 388 (M−H).

¹H NMR (DMSO-d₆) δ 12.60 (1H, brs); 8.00 (1H, m); 7.48 (3H, m); 7.21(3H, m); 6.41 (1H, m); 3.66 (1H, m); 2.59 (3H, s); 2.50 (3H, s); 2.04(1H, m); 1.56 (1H, m); 1.54 (1H, m); 1.11(1 H, m); 0.95 (1H, m); 0.69(3H, m).

Example 162 Preparation of3-(2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]dihydrofuran-2(3H)-one

To a solution of methyl2-[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxymethylether-butanoate(0.361 g; 0.82 mmol) in methanol (8.2 mL) was added a solution of sodiumhydroxide 10 N (0.82 ml) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was acidified with 1N HCl (pH-2) andpartially concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel using a gradient of methanol (1 to 20%) in dichloromethane(+0.5% AcOH) to afford 0.031 g (10%) of the title compound as a lightyellow solid.

ESI/APCI(+): 380 (M+H); 402 (M+Na).

ESI/APCI(−): 378 (M−H).

Example 163 Preparation of2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoicacid

To a solution of methyl2-[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoate(0.177 g; 0.43 mmol) in methanol (4.3 mL) was added a solution of sodiumhydroxide 10 N (0.43 ml) and the mixture was heated to 60° C. for 18 h.After cooling, the reaction mixture was acidified with 1N HCl (pH-2) andpartially concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel using a gradient of methanol (1 to 20%) in dichloromethane(+0.5% AcOH) to afford 0.032 g (19%) of the title compound as a lightyellow solid.

ESI/APCI(+): 396 (M+H).

ESI/APCI(−): 394 (M−H).

Example 164 Preparation of2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylaceticacid

To a solution of methyl2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylacetate(0.077 g; 0.18 mmol) in methanol (1.8 mL) was added a solution of sodiumhydroxide 10 N (0.18 ml) and the mixture was heated to 60° C. for 18 h.After cooling, the reaction mixture was acidified with 1N HCl (pH-2) andpartially concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was crystallized from a mixture ofethyl acetate/heptane to afford 0.029 g (40%) of the title compound as awhite solid.

ESI/APCI(+): 406 (M+H).

Example 165 Preparation of2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acrylicacid

To a solution of methyl2-[2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate(0.307 g; 0.88 mmol) in methanol (8.8 mL) was added a solution of sodiumhydroxide 10 N (0.88 ml) and the mixture was heated to 60° C. for 18 h.After cooling, the reaction mixture was acidified with 1N HCl (pH-2) andpartially concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was crystallized from a mixture ofethyl acetate/heptane to afford 0.175 g (68%) of the title compound as awhite solid.

ESI/APCI(+): 350 (M+H).

ESI/APCI(−): 348 (M−H).

Example 166 Preparation of2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoicacid

To a solution of methyl242-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate(0.124 g; 0.31 mmol) in methanol (3.1 mL) was added a solution of sodiumhydroxide 10 N (0.31 ml) and the mixture was heated to 50° C. for 18 h.After cooling, the reaction mixture was carefully acidified with 1N HCl(pH-2) and partially concentrated under reduced pressure. The residuewas partitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was crystallized from a mixture ofethyl acetate/heptane to afford 0.038 g (32%) of the title compound as abeige powder.

ESI/APCI(+): 382 (M+H).

ESI/APCI(−): 380 (M−H).

Example 167 Preparation of2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.194 g; 0.42 mmol) in methanol (4.2 mL) was added a solution of sodiumhydroxide 10 N (0.42 ml) and the mixture was heated to 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure and the crude solid was suspended in ethyl acetate and themixture was acidified with 1N HCl (pH-2). The organic layer was washedwith brine, dried over sodium sulphate, filtered and concentrated underreduced pressure. The residue was purified by preparative thin layerchromatography silica using a mixture ethyl acetate/heptane (1/1) +0.5%acetic acid as eluent to afford 0.072 g (39%) of the title compound as awhite solid.

ESI/APCI(+): 442 (M+H).

Example 168 Preparation of2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid and Example 169- Preparation of2-[2-methyl-7-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

A mixture of 4-methylbenzoylacetonitrile (0.114 g; 0.716 mmol),3-methylcyclopentanone (0.077 mL; 0.717 mmol), sulfur (0.025 g; 1.10mmol) and morpholine (0.063 mL; 0.723 mmol) in ethanol (0.57 mL) washeated at 60° C. in a sealed tube until disappearance of the defaultcompound. After cooling to room temperature, the reaction mixture waspoured into water and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate, filtered and concentrated under reducepressure. The residue was purified by flash chromatography on silica gelusing a gradient of ethyl acetate (0-25%) in heptane to afford 0.148 g(76%) of a mixture of(2-Amino-5-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-p-tolyl)methanoneand(2-Amino-6-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)(4-p-tolyl)methanoneas a yellow solid.

ESI/APCI(+): 272 (M+H).

ESI/APCI(−): 270 (M−H).

To a solution of the previous mixture (0.148 g; 0.545 mmol) and methyllevunilate (0.070 mL; 0.565 mmol) in DMF (2.7 mL) placed in a safetypressure tube was slowly added chlorotrimethylsilane (0.280 mL; 2.19mmol). The tube was sealed and heated at 100° C. for 18 h. After coolingto room temperature, the reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a saturatedsolution of sodium hydrogen carbonate, water and brine, dried oversodium sulphate, filtered and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel using agradient of ethyl acetate (0-40%) in heptane to afford 0.1 g of amixture of methyl thieno[2,3-b]pyridin-3-yl]acetate (50%).

ESI/APCI(+): 366 (M+H).

ESI/APCI(−): 364 (M−H).

To a solution of the previous mixture (0.100 g; 0.274 mmol) in dry DMF(1 mL) cooled at -10° C. was slowly added a 1N solution of LHMDS in THF(0.035 mL; 0.035 mmol). Then, 1-iodopropane (0.045 mL; 0.462 mmol) wasadded and the reaction mixture was stirred at room temperature for 6 h.The reaction was quenched by addition of a saturated solution ofammonium chloride and the reaction mixture was extracted with ethylacetate. The organic layer was washed with water and brine, dried oversodium sulphate, filtered and concentrated under reduced pressure. Thecrude residue was used without further purification.

ESI/APCI(+): 408 (M+H); 430 (M+Na).

ESI/APCI(−): 406 (M−H).

To a solution of the above crude mixture (0.105 g; 0.258 mmol) in amixture methanol-water (5 mL/ 0.25 mL) was added a solution of sodiumhydroxide 10 N (0.25 ml) and the mixture was heated at 65° C. for 12 h.After cooling, the reaction mixture was carefully acidified with 1N HCl(pH-2) and partially concentrated under reduced pressure. The residuewas partitioned between ethyl acetate and water. The organic layer waswashed with brine, dried over sodium sulphate, filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLC toafford 0.015 g (15%) of2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid (EXAMPLE 27) and 0.020 g (20%) of2-[2-methyl-7-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid.

ESI/APCI(+): 394 (M+H).

ESI/APCI(−): 392 (M−H).

2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

¹H NMR (CDCl3) δ 7.22 (3H, m); 7.06 (1H, m); 3.88 (1H, t); 3.08 (1H, m);2.74-2.63 (1H, m); 2.63 (3H, s); 2.56-2.40 (1H, m); 2.44 (3H, s);2.21-1.96 (2H, m); 1.78-1.47 (2H, m); 1.37-1.18 (1H, m); 1.14-0.94 (4H,m); 0.76 (3H, m).

2-[2-methyl-7-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

¹H NMR (CDCl₃) δ 7.22 (3H, m); 7.06 (1H, m); 3.88 (1H, m); 3.32 (1H, m);2.64 (3H, s); 2.42 (3H, s); 2.43-2.36 (1H, m); 2.12-2.06 (2H, m);1.97-1.79 (1H, m); 1.74-1.63 (2H, m); 1.26 (3H, m); 1.14-0.96 (2H, m);0.76 (3H, m).

Example 170 Preparation of2-[2-Methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution ofMethyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.335 g, 0.907 mmol) in methanol (9 mL) was added a solution of sodiumhydroxide 10 N (0.9 ml) and the mixture was heated at 100° C. for 18 hin a sealed tube. After cooling, the reaction mixture was acidified with1N HCl (pH-2) and partially concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over sodium sulphate, filtered andconcentrated under reduced pressure. The residue was crystallized from amixture of ethyl acetate/heptane to afford 0.219 g (68%) of the titlecompound as a white solid.

ESI/APCI(+): 356 (M+H).

ESI/APCI(−): 354 (M−H).

Example 171 Preparation of2-[2-Methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.249 g, 0.646 mmol) in methanol (6.5 mL) was added a solution ofsodium hydroxide 10 N (0.65 ml) and the mixture was heated at 100° C.for 18 h in a sealed tube. After cooling, the reaction mixture wasacidified with 1N HCl (pH-2) and partially concentrated under reducedpressure. The residue was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over sodium sulphate,filtered and concentrated under reduced pressure. The residue wascrystallized from a mixture of ethyl acetate/heptane to afford 0.174 g(72%) of the title compound as a white solid.

ESI/APCI(+): 372 (M+H).

ESI/APCI(−): 370 (M−H).

Example 172 Preparation of2-[2-Methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution ofMethyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.100 g, 0.244 mmol) in methanol (2.5 mL) was added a solution ofsodium hydroxide 10 N (0.25 ml) and the mixture was heated at 100° C.for 18 h in a sealed tube. After cooling, the reaction mixture wasacidified with 1N HCl (pH-2) and partially concentrated under reducedpressure. The residue was partitioned between ethyl acetate and water.The organic layer was washed with brine, dried over sodium sulphate,filtered and concentrated under reduced pressure. The residue wascrystallized from a mixture of ethyl acetate/heptane to afford 0.067 g(92%) of the title compound as a white solid.

ESI/APCI(+): 396 (M+H).

ESI/APCI(−): 394 (M−H).

Example 173 Preparation of2-[2-Methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution ofMethyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate(0.035 g, 0.097 mmol) in ethanol (1.0 mL) was added a solution of sodiumhydroxide 10 N (0.10 ml) and the mixture was heated in a sealed tube at100° C. for 18 h. After cooling, the reaction mixture was acidified with1N HCl (pH-2) and partially concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over magnesium sulphate, filtered andconcentrated under reduced pressure. The residue was crystallized fromethyl acetate to afford 0.015 g (44%) of the title compound as a whitesolid

ESI/APCI(+): 346 (M+H).

ESI/APCI(−): 300 (M-CO₂H); 344 (M−H).

Example 174 Preparation of2-[2-Methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoicacid

To a solution of methyl242-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoate(0.089 g; 0.21 mmol) in methanol (2.1 mL) was added a solution of sodiumhydroxide 10 N (0.21 ml) and the mixture was heated at 70° C. for 4 h.After cooling, the reaction mixture was concentrated under reducedpressure and the crude solid was suspended in ethyl acetate and themixture was acidified with 1N HCl (pH-2). The organic layer was washedwith brine, dried over sodium sulphate, filtered and concentrated underreduced pressure. The residue was purified by preparative thin layerchromatography on silica using a mixture dichloromethane/methanol (98/2)+0.5% acetic acid as eluent to afford 0.029 g (35%) of the titlecompound as a white solid.

ESI/APCI(+): 396 (M+H).

Example 175 Preparation of2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoicacid

To a solution of methyl2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoate(0.159 g; 0.36 mmol) in methanol (3.6 mL) was added a solution of sodiumhydroxide 10 N (0.36 ml) and the mixture was heated at 70° C. for 4 h.After cooling, the reaction mixture was concentrated under reducedpressure and the crude solid was suspended in ethyl acetate and themixture was acidified with 1N HCl (pH-2). The organic layer was washedwith brine, dried over sodium sulphate, filtered and concentrated underreduced pressure. The residue was purified by preparative thin layerchromatography on silica using a mixture ethyl acetate/heptane (1/1)+0.5% acetic acid as eluent to afford 0.056 g (38%) of the titlecompound as a white solid.

ESI/APCI(+): 428 (M+H).

Example 176 Preparation of2-[2-Methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoic acid

To a solution of methyl [2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.434 g; 1.03 mmol) in methanol (10 mL)and water (1 mL), was added a solution of sodium hydroxide 10 N (1 mL)and the mixture was heated at 60° C. for 18 h. After cooling, thereaction mixture was concentrated under reduced pressure. The residuewas dissolved in ethyl acetate and the mixture was acidified with HCl(1N) until pH 1. The organic layer was washed with brine, water, driedover magnesium sulphate and concentrated under reduced pressure. Thecrude residue was crystallized from a mixture ethyl acetate-heptane tofurnish 0.38 g (90%) of the title compound as a light yellow solid.

ESI/APCI(+): 408 (M+H).

Example 177 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methyl-4-methylpentanoate(0.114 g; 0.27 mmol) in methanol (2.7 mL) and water (0.27 mL) was addeda solution of sodium hydroxide 10 N (0.27 mL) and the mixture was heatedat 60° C. for 18 h. After cooling, the reaction mixture was concentratedunder reduced pressure. The residue was dissolved in ethyl acetate andthe mixture was acidified with HCl (1N) until pH 1. The organic layerwas washed with brine, water, dried over magnesium sulphate andconcentrated under reduced pressure. The crude residue was crystallizedfrom a mixture ethyl acetate-heptane to furnish 0.083 g (76%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 408 (M+H).

Example 178 Preparation of2-[2-Methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.244 g; 0.57 mmol) in methanol (5.7 mL) was added a solution of sodiumhydroxide 5 N (1.14 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.222 g (94%) of the title compound asa light yellow solid.

ESI/APCI(+): 414 (M+H).

Example 179 Preparation of2-[2-Methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(3-chlorophenyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.281 g; 0.65 mmol) in methanol (6.5 mL)was added a solution of sodium hydroxide 5 N (1.3 mL) and the mixturewas heated at 60° C. for 18 h. After cooling, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in ethylacetate and the mixture was acidified with HCl (1N) until pH 1. Theorganic layer was washed with brine, water, dried over magnesiumsulphate and concentrated under reduced pressure. The crude residue wascrystallized from a mixture ethyl acetate-heptane to furnish 0.220 g(82%) of the title compound as a light yellow solid.

ESI/APCI(+): 414 (M+H).

Example 180 Preparation of2-[2-Methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.172 g; 0.37 mmol) in methanol (3.7 mL) was added a solution of sodiumhydroxide 5 N (0.74 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.121 g (73%) of the title compound asa light yellow solid.

ESI/APCI(+): 449 (M+H).

Example 181 Preparation of2-[2-Methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.233 g; 0.5 mmol) in methanol (5 mL) was added a solution of sodiumhydroxide 5 N (1 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.125 g (56%) of the title compound asa light yellow solid.

ESI/APCI(+): 448 (M+H).

Example 182 Preparation of2-[2-Methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methylR2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.281 g; 0.65 mmol) in methanol (6.5 mL) was added a solution of sodiumhydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.129 g (52%) of the title compound asa light yellow solid.

ESI/APCI(+): 394 (M+H).

Example 183 Preparation of2-[2-Methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.290 g; 0.7 mmol) in methanol (7 mL) was added a solution of sodiumhydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.276 g (99%) of the title compound asa light yellow solid.

ESI/APCI(+): 394 (M+H).

Example 184 Preparation of2-[2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoicacid

To a solution of methyl2-(6-methyl-3-phenyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanoate (0.27g; 0638 mmol) in methanol (6.3 mL) was added a solution of sodiumhydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.052 g (20%) of the title compound asa light yellow solid.

ESI/APCI(+): 416 (M+H);

ESI/APCI(−): 414 (M−H), 370 (M−H—CO₂);

Example 185 Preparation of2-[2-Methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(3-methoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.244 g; 0.577 mmol) in methanol (5.8 mL) was added a solution ofsodium hydroxide 5 N (1.15 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.160 g (68%) of the title compound asa light yellow solid.

ESI/APCI(+): 410 (M+H);

ESI/APCI(−): 408 (M−H), 364 (M−H—O₂);

Example 186 Preparation of2-[2-Methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.226 g; 0.499 mmol) in methanol (5 mL) was added a solution of sodiumhydroxide 5 N (1 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.078 g (36%) of the title compound asa light yellow solid.

ESI/APCI(+): 440 (M+H);

ESI/APCI(−): 438 (M−H);

Example 187 Preparation of2-[2-Methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.300 g; 0.686 mmol) in methanol (6.9 mL) was added a solution ofsodium hydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.168 g (58%) of the title compound asa light yellow solid.

ESI/APCI(+): 424 (M+H);

ESI/APCI(−): 422 (M−H);

Example 188 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluorohexanoate(0.172 g; 0.362 mmol) in methanol (3.6 mL) was added a solution ofsodium hydroxide 5 N (0.72 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.134 g (81%) of the title compound asa light yellow solid.

ESI/APCI(+): 462 (M+H);

ESI/APCI(−): 460 (M−H);

Example 189 Preparation of2-[2-Methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.196 g; 0.459 mmol) in methanol (4.6 mL) was added a solution ofsodium hydroxide 5 N (0.95 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.150g (76%) of the title compound as alight yellow solid.

ESI/APCI(+): 414 (M+H).

ESI/APCI(−): 412 (M−H).

Example 190 Preparation of2-[2-Methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.197 g; 0.468 mmol) in methanol (4.6 mL) was added a solution ofsodium hydroxide 5 N (0.95 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure to furnish 0.092 g (48%) of the title compound as awhite solid.

ESI/APCI(+): 409 (M+H).

ESI/APCI(−): 407 (M−H).

Example 191 Preparation of2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.058 g; 0.147 mmol) in methanol (1.5 mL) was added a solution ofsodium hydroxide 5 N (0.29 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure to furnish 0.023 g (42%) of the title compound as awhite solid.

ESI/APCI(+): 381 (M+H).

Example 192 Preparation of2-[2-Methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.271 g; 0.568 mmol) in methanol (5.7 mL) was added a solution ofsodium hydroxide 5 N (1.1 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. Purification by preparative HPLC (HPLC method 1)furnished 0.010 g (4%) of the title compound as a light yellow solid.

ESI/APCI(−): 462 (M−H).

Example 193 Preparation of2-p-Methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.129 g; 0.264 mmol) in methanol (2.6 mL) was added a solution ofsodium hydroxide 5 N (0.52 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. A purification by preparative TLC using a mixtureethyl acetate/heptane (1:1) +0.5% AcOH furnished 0.006 g (5%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 475 (M+H).

ESI/APCI(−): 473 (M−H).

Example 194 Preparation of2-[2-Methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.266 g; 0.647 mmol) in methanol (6.5 mL) was added a solution ofsodium hydroxide 5 N (1.3 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure.

Purification by preparative HPLC (HPLC method 1) furnished 0.005 g (2%)of the title compound as a light yellow solid.

ESI/APCI(+): 398 (M+H).

ESI/APCI(−): 396 (M−H).

Example 195 Preparation of2-[2-Methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.302 g; 0.697 mmol) in methanol (7 mL) was added a solution of sodiumhydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.093 g (32%) of the title compound asa light yellow solid.

ESI/APCI(+): 420 (M+H).

Example 196 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoate(0.128 g; 0.272 mmol) in methanol (2.7 mL) was added a solution ofsodium hydroxide 5 N (0.54 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. A purification by Preparative TLC using a mixtureethyl acetate/heptane (1:1) +0.5% AcOH furnished 0.003 g (2%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 456 (M+H).

ESI/APCI(−): 454 (M−H).

Example 197 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoate(0.109 g; 0.267 mmol) in methanol (2.7 mL) was added a solution ofsodium hydroxide 5 N (0.53 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. A purification by preparative TLC using a mixtureethyl acetate/heptane (1:1) +0.5% AcOH furnished 0.0013 g (12%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 394 (M+H).

ESI/APCI(−): 392 (M−H); 348 (M−H—CO₂).

Example 198 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methypentanoate(0.108 g; 0.256 mmol) in methanol (2.5 mL) was added a solution ofsodium hydroxide 5 N (0.5 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. A purification by preparative TLC using a mixtureethyl acetate/heptane (1:1) +0.5% AcOH furnished 0.038 g (36%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 408 (M+H).

ESI/APCI(−): 406 (M−H).

Example 199 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoate(0.061 g; 0.132 mmol) in methanol (1.3 mL) was added a solution ofsodium hydroxide 5 N (0.26 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. A purification by preparative TLC using a mixtureethyl acetate/heptane (1:1) +0.5% AcOH furnished 0.0024 g (9%) of thetitle compound as a light yellow solid.

ESI/APCI(+): 448 (M+H).

ESI/APCI(−): 446 (M−H).

Example 200 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yn-oicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pent-4-yn-oate(0.146 g; 0.362 mmol) in methanol (3.6 mL) was added a solution ofsodium hydroxide 5 N (0.72 mL) and the mixture was heated at 60° C. for18 h. After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. Purification by preparative HPLC (HPLC method 1)furnished 0.0023 g (2%) of the title compound as a light yellow solid.

ESI/APCI(+): 390 (M+H).

ESI/APCI(−): 388 (M−H).

Example 201 Preparation of2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of methyl[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.108 g; 0.25 mmol) in methanol (2.5 mL) was added a solution of sodiumhydroxide 5 N (0.5 mL) and the mixture was heated at 60° C. for 18 h.After cooling, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and the mixture wasacidified with HCl (1N) until pH 1. The organic layer was washed withbrine, water, dried over magnesium sulphate and concentrated underreduced pressure. The crude residue was crystallized from a mixtureethyl acetate-heptane to furnish 0.077 g (76%) of the title compound asa white solid.

ESI/APCI(+): 424 (M+H).

ESI/APCI(−): 422 (M−H).

Example 202 Preparation of2-[2-Methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]pentanoateammonium salt and2-[2-methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a solution of boron tribromide (1M in dichloromethane) (0.75 mL; 0.75mmol) in dry dichloromethane (0.25 mL) at −30° C. under nitrogenatmosphere was slowly added a solution of methyl[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.108 g; 0.25 mmol) in dry dichloromethane (1 mL). The reaction mixturewas stirred at 0° C. under nitrogen until completion. The reaction wasthen quenched by addition of methanol and the reaction mixture waswashed with a saturated solution of sodium hydrogencarbonate. Theorganic layer was separated and the aqueous phase was extracted withethyl acetate. The organics were collected and acidified with HCl (1N)until pH 2. The organic layer was dried over magnesium sulphate andconcentrated under reduced pressure. Purification by preparative HPLC(HPLC method 3) furnished 0.008 g (8%) of the title compound as a whitesolid.

ESI/APCI(+): 410 (M+H).

ESI/APCI(−): 408 (M−H).

The2-[2-methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid can be obtained from the242-methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoateammonium salt by simple extraction between ethyl acetate and HCl (1N).The organic layer is then dried over anhydrous magnesium sulphate,filtered and evaporated to dryness to provide the desired compound(quantitative) as a dry powder.

ESI/APCI(+): 410 (M+H).

ESI/APCI(−): 408 (M−H).

Example 203 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoicacid

To a solution of methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate(0.039 g; 0.089 mmol) in methanol (2.7 mL) was added a 5% sodiumhydroxide solution (2.68 mmol; 2.15 mL) and the reaction mixture washeated at 60° C. 18 h. An extra volume of 5% sodium hydroxide solution(1 mL) and ethanol (1 mL) were added and the reaction mixture was heatedat 60° C. for 12 additional hours. After cooling, the volatiles wereremoved under reduced pressure and the residue was dissolved in water.The mixture was acidified with HCl (1N) until pH 2 and the aqueous layerwas extracted with ethyl acetate. The organics were combined, dried overmagnesium sulphate and concentrated under reduced pressure. The whitesolid was crystallized in a mixture ethyl acetate-heptane to furnish0.025 g (67%) of the title compound as a white solid.

ESI/APCI(+): 422 (M+H).

ESI/APCI(−): 420 (M−H).

Example 204 Preparation of2-[7-Benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid

To a suspension of ethyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate(0.514 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was addeda 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixturewas heated at reflux for 18 h. After cooling, the organic volatiles wereremoved under reduced pressure and the remaining basic solution wasacidified with HCl (1N) until pH 2 and the aqueous layer was extractedwith ethyl acetate. The organics were combined, dried over magnesiumsulphate and concentrated under reduced pressure. Purification bypreparative HPLC (HPLC method 2) furnished 0.027g (5.5%) of the titlecompound as a light yellow solid.

ESI/APCI(+): 487 (M+H).

Example 205 Preparation of2-[2,7-Dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid

To a suspension of ethyl[2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate(0.438 g; 1 mmol) in a mixture methanol-ethanol (2:1) (15 mL) was addeda 5% sodium hydroxide solution (15 mmol; 12 mL) and the reaction mixturewas heated at reflux for 18 h. After cooling, the organic volatiles wereremoved under reduced pressure and the remaining basic solution wasacidified with HCl (1N) until pH 2 and the aqueous layer was extractedwith ethyl acetate. The organics were combined, dried over magnesiumsulphate and concentrated under reduced pressure. Purification bypreparative HPLC (HPLC method 2) furnished 0.024 g (5.8%) of the titlecompound as a yellow oil.

ESI/APCI(+): 411 (M+H).

Example 206 Preparation of2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydroMbenzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoicacid

To a suspension of ethyl242-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate(0.035 g; 0.080 mmol) in a mixture methanol-ethanol (2:1) (2.4 mL) wasadded a 5% sodium hydroxide solution (1.94 mL; 2.42 mmol) and thereaction mixture was heated to 90° C. for 6 h. The organic volatileswere removed under reduced pressure and the remaining basic solution wasacidified with HCl (1N) until pH 2. The white precipitate was filteredand dried to furnish 0.025 g (76%) of the title compound as a whitesolid.

ESI/APCI(+): 406 (M+H).

Example 207 Preparation ofN-cyano-2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide

A mixture of2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoaicacid (0.101 g; 0.257 mmol) in thionyl chloride (1 mL) and 1 drop of DMFwas heated at 65° C. for 1 h. The volatiles were evaporated and theresidue was dissolved in dichloromethane (2 mL). Diisopropylethylamine(0.200 mL; 1.15 mmol) and cyanamide (0.0275 g; 0.654 mmol) were addedand the solution was stirred for 20 h. Ethyl acetate was added to thereaction mixture and the solution was washed with a HCl (1N) and brine.The organic layer was dried over magnesium sulphate, filtered andconcentrated under reduced pressure. Purification byflash-chromatography on silica using a gradient of methanol (0-7%) indichloromethane furnished 0.104 g (46%) of the title compound as asolid.

ESI/APCI (+): 418 (M+H).

ESI/APCI (−): 416 (M−H).

¹H-NMR (400 MHz, DMSO-d₆) (ppm) δ: 10.9 (bs, 1H, NH); 7.30 (m, 3H,Harom.); 7.08 (m, 1H, Harom.); 3.78 (m, 1H, CH); 2.63 (s, 3H, CH₃););2.63 (s, 3H, CH₃);1.8-0.7 (m, 12H, Hcyclohexyl+2×CH₂); 0.81 (t, 3H,CH₃).

Example 208 Preparation of2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide

A mixture of242-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoaicacid (0.106 g; 0.269 mmol) in thionyl chloride (1.5 mL) was heated at65° C. for 1 h. The volatiles were evaporated and the residue wasdissolved in dichloromethane (1 mL) and cooled at 0° C. A 0.5 M ammoniasolution in THF (3 mL; 1.50 mmol) was added and the solution was stirredfor 1 h. The volatiles were removed under reduced pressure and ethylacetate and a HCl (1N) added to the residue. Both phases were separatedand the organic layer was washed with a solution of sodiumhydrogencarbonate (1N) and brine, dried over magnesium sulphate,filtered and evaporated under reduced pressure. Purification byflash-chromatography on silica using a gradient of methanol (0-5%) indichloromethane furnished 0.084 g (79%) of the title compound as a paleyellow oil.

ESI/APCI (+): 393 (M+H).

ESI/APCI (−): 391 (M−H).

Example 209 Preparation of Intermediate Ethyl2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

To a solution of ethyl cyanoacetate (42.68 mL; 400 mmol) in dry ethanol(400 mL) were added cyclohexanone (62.18 mL; 600 mmol), morpholine (52.8mL; 600 mmol) and sulfur (19.24 g; 600 mmol). The reaction mixture wasstirred at room temperature for 48 h and the resulting suspension wasfiltered, washed with a small volume of cold ethanol and dried tofurnish 66 g (73%) of the title compound as a white powder.

ESI/APCI(+): 226 (M+H).

Example 210 Preparation of IntermediateEthyl(4-hydroxy-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate

To a solution of ethyl2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (33.8 g; 150mmol) and ethyl-3-ethoxybut-2-enoate (25 g; 157.5 mmol) in xylene (600mL) was added a catalytic amount of p-toluenesulfonic acid mono hydrate.The resulting reaction mixture was heated to reflux (temp. of bath 165°C.) equipped with a Dean-Stark trap and condenser to collect ethanol.After 18 h, the solution was cooled to room temperature, transferred toa dropping funnel and then added dropwise to a stirred solution ofsodium ethoxide (21% in ethanol, 59 mL; 157.5 mmol) in ethanol (350 mL).The resulting solution is heated to reflux for 18 h and, after cooling,the volatiles were removed under reduced pressure to yield a black oil.This material was suspended in water (150 mL) and washed withdiethylether (2×150 mL). The aqueous phase was separated, cooled at 0°C. and slowly acidified to pH 4 with a 1N HCl with rapid stirring. Theresulting precipitate was filtered, washed with diluted hydrochloricacid solution and dried to furnish 25.5 g (58%) of the title compound asa black solid.

ESI/APCI(+): 292 (M+H).

ESI/APCI(−): 290 (M−H).

Example 211 Preparation of IntermediateEthyl(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate

Theethyl(4-hydroxy-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate(2.45 g; 8.41 mmol) was suspended in phosphorus oxychloride (15.7 mL;168.17 mmol) and the mixture was heated at 100° C. for 40 min. Aftercooling, the excess of phosphorus oxychloride was removed under reducedpressure, the residue was diluted in ethyl acetate and washed with asaturated solution of sodium hydrogencarbonate, brine and water. Theorganic layer was dried over sodium sulphate and concentrated underreduced pressure. Purification by flash-chromatography on silica gelusing a gradient of ethyl acetate (0-40%) in dichloromethane furnished1.79 g (68%) of the title compound as a dark oil.

ESI/APCI(+): 310-312 (M+H).

Example 212 Preparation of Intermediate(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methanol

To a solution ofethyl(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate(1.79 g; 5.78 mmol) in dry dichloromethane (18 mL) at −78° C. undernitrogen atmosphere was added a 1M solution of diisobutylaluminiumhydride in dichloromethane (13.3 mL; 13.29 mmol). The resulting solutionwas stirred for 1.5 h and 1 h more at 0° C. The reaction mixture wasquenched by adding 1N HCl carefully (17 mL) and the resulting mixturewas vigorously stirred for 1 h. The phases were separated and theaqueous layer was extracted with dichloromethane. The organics werecombined and washed with a Rochelle's salt solution and brine, driedover sodium sulphate, concentrated under reduced pressure to furnish 1.2g (77%) of the title compound as an orange solid.

ESI/APCI(+): 268-270 (M+H).

Example 213 Preparation of Intermediate(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carbaldehyde

To a cold (10° C.) solution of(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methanol(2.14 g; 8 mmol) in dry dimethylsulfoxide (15 mL) under nitrogenatmosphere was added triethylamine (3.37 mL; 24 mmol) followed by Py.SO₃complex (3.20 g; 20 mmol). The resulting mixture was stirred at roomtemperature for 1 h and then poured with water (60 mL). The mixture wasfiltered, washed with water and dried under reduced pressure to furnish1.95 g (92%) of the title compound as a beige solid.

ESI/APCI(+): 266-268 (M+H).

Example 214 Preparation of Intermediate2-(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)-2-(trimethylsilyloxy)acetonitrile

To a cold (0° C.) mixture of(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carbaldehyde(1.95 g; 7.3 mmol) in dichloromethane (40 mL) was added zinc iodide(1.17 g; 3.67 mmol) followed by trimethylsilylcyanide (2.94 mL; 22.01mmol). The reaction mixture was stirred at room temperature for 1.5 h,diluted with dichloromethane (40 mL) and quenched with water (30 mL).The aqueous layer was extracted with dichloromethane and the combinedorganics were washed with water and brine, dried over sodium sulphateand concentrated under reduced pressure to furnish 2.5 g (93%) of thetitle compound as a brown oil.

ESI/APCI(+): 365-367 (M+H).

Example 215 Preparation of Intermediate Methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate

To a cooled (0° C.), stirred solution of methanol (85 ml) under an argonatmosphere was added dropwise acetyl chloride (12.1 ml; 170 mmol). Thesolution was warmed to room temperature and used immediately to dissolve2-(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)-2-trimethylsilyloxy)acetonitrile(6.02 g; 16.4 mmol). The resulting mixture was heated at reflux for 24h. After cooling, the volatiles were removed under reduced pressure, theremaining residue was partitioned between ethyl acetate and a saturatedsodium bicarbonate solution. The phases were separated and the aqueouslayer was extracted with ethyl acetate. The combined organics werewashed with a saturated sodium chloride solution, dried over magnesiumsulphate and concentrated under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of ethylacetate(10-80%) in heptane furnished 3,2 g (59.5%) of the title compound as alight brown solid.

ESI/APCI(+): 326 (M+H).

Example 217 Preparation of Intermediate Methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate(0.100 g, 0.307 mmol) in tert-butyl acetate (1,5 mL; 11,23 mmol) under anitrogen atmosphere was added perchloric acid 70% (0.029 mL; 0.338mmol). The reaction was stirred at room temperature for 5 h and quenchedby adding a saturated solution of sodium bicarbonate. The mixture wasdiluted with dichloromethane and the phases were separated. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. Purification by flash-chromatography on silica gel using agradient of ethylacetate (5-40%) in heptane furnished 0.069 g (59%) ofthe title compound as a solid.

ESI/APCI(+): 382 (M+H).

Example 218 Preparation of Intermediate Methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate

To a cold solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate(0.100 g; 0.307 mmol) in dry DMF (1.5 ml) at −15° C. under nitrogenatmosphere was added LHMDS (1M in THF) (0.338 mL; 0.338 mmol) dropwiseand the mixture was stirred at −15° C. for 15 min. Then, iodoethane(0.049 mL; 0.614 mmol) was added and the mixture was allowed to warm upto room temperature. After 72 h, the reaction was quenched by adding asaturated solution of ammonium chloride, extracted with dichloromethaneand the combined organics were washed with brine, dried over magnesiumsulphate and concentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethylacetate (5-40%) inheptane furnished 0.040 g (37%) of the title compound as a solid.

ESI/APCI(+): 354 (M+H).

Example 219 Preparation of Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.069 g; 0.181 mmol) in a mixture of DME-water (3:1) (1mL) were addedpotassium carbonate (0.100 g; 0.723 mmol),tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol) and4-tolylboronic acid (0.049 g; 0.361 mmol). The solution was stirred for30 min at 140° C. under microwave irradiation. Ethyl acetate was addedto the reaction mixture and the solution was washed with brine. Theorganic phase was dried over magnesium sulphate, filtered andconcentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethylacetate (5-40%) inheptane furnished 0.043 g (44%) of the title compound as a solid.

ESI/APCI(+): 438 (M+H).

Example 220 Preparation of Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate(0.040 g; 0.113 mmol) in a mixture of DME-water (3:1) (0.48 mL) wereadded potassium carbonate (0.062 g; 0.452 mmol),tetrakis(triphenylphosphine)palladium(0) (0.0065 g; 0.0056 mmol) and4-tolylboronic acid (0.031 g; 0.226 mmol). The solution was stirred for30 min at 140° C. under microwave irradiation. Ethyl acetate was addedto the reaction mixture and the solution was washed with brine. Theorganic phase was dried over magnesium sulphate, filtered andconcentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethylacetate (5-40%) inheptane furnished 0.025 g (54%) of the title compound as a solid.

ESI/APCI(+): 410 (M+H).

Example 221 Preparation of2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.043 g; 0.098 mmol) in methanol (1 mL) was added a solution of sodiumhydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated to 60° C.for 18 h. The volatiles were removed under reduced pressure and theresidue was dissolved in water, the mixture was then acidified by adding1N HCl until a precipitate was formed. The solid was filtered, washedwith water and dried under reduced pressure. The crude product wassuspended in a mixture of acetonitrile and methanol, filtered, washedwith acetonitrile and dried under reduced pressure to furnish 0.012 g(28%) of the title compound as a white solid.

ESI/APCI(+): 424 (M+H).

ESI/APCI(−): 422 (M−H).

Example 222 Preparation of2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyaceticacid

To a solution of methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate(0.025 g; 0.061 mmol) in methanol (0.75 mL) was added a solution ofsodium hydroxide 10 N (0.075 mL; 0.750 mmol) and the mixture was heatedat 60° C. for 18 h. The volatiles were removed under reduced pressureand the residue was dissolved in water, the mixture was then acidifiedby adding 6N HCl until a precipitate was formed. The solid was filtered,washed with water and dried under reduced pressure to furnish 0.013 g(52%) of the title compound as a white solid.

ESI/APCI(+): 396 (M+H).

ESI/APCI(−): 395 (M−H).

Example 223 Preparation of Methyl2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1mL) were addedpotassium carbonate (0.145 g; 1.047 mmol),tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.0013 mmol) and3-pyridinylboronic acid (0.064 g; 0.524 mmol). The solution was stirredfor 30 min at 140° C. under microwave irradiation. Ethyl acetate wasadded to the reaction mixture and the solution was washed with brine.The organic phase was dried over magnesium sulphate, filtered andconcentrated under reduced pressure.

Purification by flash chromatography on silica gel using a gradient ofethylacetate (2-20%) in heptane furnished 0.052 g (47%) of the titlecompound as a solid.

ESI/APCI(+): 425 (M+H).

Example 224 Preparation of2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.052 g; 0.122 mmol) in methanol (1.5 mL) was added a solution ofsodium hydroxide 10 N (0.150 mL; 1.5 mmol) and the mixture was heated to60° C. for 18 h. The volatiles were removed under reduced pressure andthe residue was dissolved in water, the mixture was then acidified byadding 1N HCl until a precipitate was formed. The solid was filtered,washed with water and dried under reduced pressure to furnish 0.032 g(61%) of the title compound as a white solid.

ESI/APCI(+): 409 (M+H).

Example 225 Preparation of2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanenitrile

Triethylamine (0.100 mL; 0.712 mmol) was added to a solution of2-(2,3-tetramethylene-6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanamide(0.080 g; 0.204 mmol) in dry dichloromethane (8 mL). The solution wascooled to 0° C. and trifluoroacetic anhydride (0.050 mL; 0.359 mmol) wasadded dropwise to the cold solution. The solution was allowed to warm upto room temperature over 3 h. The reaction mixture was washed with asolution of HCl (1N), with a solution of sodium hydrogencarbonate (1N)and brine, dried over magnesium sulphate, filtered and evaporated untildryness. The crude material was used in the next step without furtherpurification.

Example 226 Preparation of2-Methyl-4-(p-tolyl)-3-[1-(1H-tetrazol-5-yl)butyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine

To a solution of2-(2,3-tetramethylene-6-methyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)pentanenitrile(0.076 g; 0.203 mmol) in DMF (2 mL) were added sodium azide (0.042 g;0.646 mmol) and ammonium chloride (0.046 g; 0.860 mmol) and the mixturewas heated at 110° C. for 6 days. The reaction mixture was poured intoice-water (20 mL), acidified with 1N HCl (5 mL) and extracted with ethylacetate (2×15 mL). The combined organic layers were washed with brine,dried over magnesium sulphate, filtered and evaporated until dryness.Purification by preparative HPLC (HPLC method 1) furnished 0.035 g (41%)of the title compound as a white solid.

ESI/APCI (+): 418 (M+H).

ESI/APCI (−): 416 5M−H).

Example 227 Preparation of Methyl2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (1 mL) were addedpotassium carbonate (0.109 g; 0.786 mmol),tetrakis(triphenylphosphine)palladium(0) (0.015 g; 0.013 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.109 g; 0.524 mmol). The solution was stirred for 30 min at 140° C.under microwave irradiation. Ethyl acetate was added to the reactionmixture and the solution was washed with brine. The organic phase wasdried over magnesium sulphate, filtered and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethylacetate (5-80%) in heptane furnished 0.065 g (58%) ofthe title compound as a light yellow oil.

ESI/APCI(+): 428 (M+H).

Example 228 Preparation of2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.120 g; 0.281 mmol) in methanol (3.5 mL) was added a solution ofsodium hydroxide 10 N (0.350 mL; 3.5 mmol) and the mixture was heated at60° C. for 18 h. The volatiles were removed under reduced pressure andthe residue was dissolved in water, the mixture was then acidified byadding 1N HCl until a precipitate was formed. The solid was filtered,washed with water and dried under reduced pressure. The crude productwas suspended in a mixture of acetonitrile and methanol, filtered,washed with acetonitrile and dried under reduced pressure to furnish0.034 g (29%) of the title compound as a white solid.

ESI/APCI(+): 411 (M+H).

ESI/APCI(−): 409 (M−H).

Example 229 Preparation of3-(1-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]butyl)-1,2,4-oxadiazol-5(4H)-one

A solution of2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanenitrile(0.082 g; 0.219 mmol) in methanol (1 mL) was treated with hydroxylaminehydrochloride (0.023 g; 0.331 mmol) and sodium bicarbonate (0.026 mg;0.310 mmol) and the mixture was heated at 65° C. for 18 h. The volatileswere evaporated and the residue was dissolved in ethyl acetate, washedwith brine, dried over magnesium sulphate, filtered and concentratedunder reduced pressure to afford the crudeN′-hydroxy-2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanimidamidewhich was mixed with carbodiimidazole (0.050 g; 0.308 mmol) in dioxane(2 mL) and heated at 100° C. for 45 min. The volatiles were removedunder reduced pressure and the residue was dissolved in ethyl acetate,washed with brine, dried over magnesium sulphate, filtered andconcentrated under reduced pressure. Purification by preparative HPLC(HPLC method 1) furnished 0.023 g (25%) of the title compound as a whitesolid.

ESI/APCI (+): 434 (M+H).

ESI/APCI (−): 432 (M−H).

Example 230 Preparation of Ethyl[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

To a solution of(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone(0.542 g; 2 mmol) and ethyl 4-oxohexanoate (0.348 g; 2.2 mmol) in dryDMF (8 mL) under a nitrogen atmosphere was added chlorotrimethylsilane(1.02 mL; 8 mmol) dropwise. The mixture was stirred in a sealed tube andheated at 100° C. for 24 h. After cooling to room temperature, thereaction mixture was partitioned between ethyl acetate and water. Theorganic phase was successively washed with a saturated solution ofsodium hydrogen carbonate, water, brine, dried over sodium sulphate,filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel column using a gradientof ethyl acetate (1-30%) in heptane to afford 0.508 g (64%) of the titlecompound as a yellow oil.

ESI/APCI(+): 394 (M+H).

Example 231 Preparation of Ethyl2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

To a solution of ethyl[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate(0.491 g; 1.25 mmol) in dry DMF (5 mL) at −10° C. was added a 1Nsolution of LHMDS in THF (1.38 mL; 1.38 mmol) and 1-propyliodide (0.183mL; 1.88 mmol). The reaction mixture was allowed to warm up to roomtemperature and the stirring was carried on for 3 h. The reactionmixture was quenched by addition of a saturated solution of ammoniumchloride and the mixture was extracted with ethyl acetate. The organiclayer was washed with water, brine, dried over sodium sulphate, filteredand concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel to afford 0.322 g (59%) of the titlecompound as a light yellow oil.

ESI/APCI(+): 436 (M+H).

Example 232 Preparation of2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

To a suspension of ethyl2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate(0.322 g; 0.739 mmol) in a mixture methanol-ethanol (2:1) (22.5 mL) wasadded a solution of sodium hydroxide 5% (18 mL; 22.5 mmol) and thereaction mixture was heated at 90° C. for 4 h. The organic volatileswere removed under reduced pressure and the remaining basic solution wasacidified until pH 2 with a solution of hydrochloric acid 1N. Theaqueous layer was extracted with ethyl acetate, the organics werecombined, dried over sodium sulphate and concentrated under reducedpressure to furnish 0.203 g (68%) of the title compound as a whitesolid.

ESI/APCI(+): 408 (M+H).

Example 233 Preparation of Intermediate5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione

To a solution of(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carbaldehyde(0.102 g; 0.318 mmol) in ethanol (2 mL) were added1,3-thiazoline-2,4-dione (0.040 g; 0.342 mmol) and piperidine (0.010 mL;0.101 mmol) and the reaction mixture was stirred at 80° C. for 24 h.After slow cooling, the solution was poured in water, acidified with asolution of hydrochloric acid 1N and extracted with ethyl acetate. Theorganics were combined, washed with brine, dried over magnesiumsulphate, filtered and concentrated under reduced pressure to furnish0.083 g (62%) of the title compound, which was used in the next reactionwithout further purification.

ESI/APCI (+): 421 (M+H).

Example 234 Preparation of5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butyl]thiazolidine-2,4-dione

To a cold (−15° C.) solution of copper(I)iodide (0.200 g; 1.05 mmol) inanhydrous diethyl ether (5 mL) was added a 2M solution ofn-propylmagnesium chloride in diethyl ether (1.0 mL; 2.0 mmol). Themixture was stirred for 20 min and a solution of5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylene]thiazolidine-2,4-dione(0.083 g; 0.197 mmol) in a mixture diethyl ether-tetrahydrofurane (2/1,3 mL) was added dropwise and stirring was carried on for 2 h at −15° C.and 18 h at room temperature. The reaction was quenched with a saturatedsolution of ammonium chloride (50 mL) and diluted with diethyl ether (20mL). Both phases were separated, the aqueous layer was extracted withdiethyl ether, the combined organic phases were washed with a saturatedsolution of ammonium chloride, dried over magnesium sulphate, filteredand concentrated under reduced pressure. Purification by preparativeHPLC (HPLC method 1) furnished 0.008 g (9%) of the title compound.

ESI/APCI (+): 465 (M+H).

Example 235 Preparation of Intermediate Ethyl(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate

To a solution of ethyl(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate(10 g; 32.3 mmol) in tetrahydrofurane (100 ml) at room temperature wasslowly added a 4N solution of hydrochloric acid in dioxane (56.5 mL; 226mmol). The mixture was stirred at 60° C. for 1 h and then concentratedunder reduced pressure. The residue was dissolved in acetonitrile (75mL), sodium iodide (38.7 g; 258 mmol) was added and the mixture washeated at reflux for 48 h. The volatiles were removed under reducedpressure, the residue dissolved in ethyl acetate and was successivelywashed with water, a solution of sodium thiosulphate, water and brine.The organics were dried over magnesium sulphate, filtered andconcentrated under reduced pressure to afford 10.83 g (71%) of the titlecompound as a yellow solid.

ESI/APCI(+): 402 (M+H).

Example 236 Preparation of Intermediate(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl)methanol

To a solution of ethyl(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate(10.83 g; 27 mmol) in dry dichloromethane (90 mL) at −78° C. undernitrogen atmosphere was added a 1M solution of diisobutylaluminiumhydride in dichloromethane (59.4 mL; 59.4 mmol). The resulting solutionwas stirred for 1 h, allowed to warm up to 0° C. and stirred for 2additional hours at 0° C. The reaction mixture was quenched by adding asolution of hydrochloric acid 1N (17 mL) carefully and the resultingmixture was vigorously stirred for 1 h. The phases were separated andthe aqueous layer was extracted with dichloromethane. The organics werecombined and washed with a Rochelle's salt solution and brine, driedover sodium sulphate and concentrated under reduced pressure.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (0-80%) in heptane furnished 3.4 g (35%) of the titlecompound as a yellow solid.

ESI/APCI(+): 360 (M+H). EXAMPLE 237

Preparation of Intermediate(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carbaldehyde

To a cold (10° C.) solution of(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methanol(3.04 g; 8.46 mmol) in dry dimethylsulfoxide (20 mL) under a nitrogenatmosphere was added triethylamine (3.57 mL; 25.4 mmol) followed byPy.SO₃ complex (3.37 g; 21.16 mmol). The resulting mixture was stirredat room temperature for 1 h and then poured in water (80 mL). Themixture was filtered, washed with water and dried under reduced pressureto furnish the title compound as a beige solid. The crude material wasused in the next reaction without further purification.

ESI/APCI(+):358 (M+H).

Example 238 Preparation of Intermediate2-(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl)-2-(trimethylsilyloxy)acetonitrile

To a cold (0° C.) mixture of(4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carbaldehyde(3.02 g; 8.46 mmol) in dichloromethane (42 mL) was added zinc iodide(1.35 g; 4.23 mmol) followed by trimethylsilylcyanide (2.27 ml; 16.92mmol). The reaction mixture was stirred at room temperature for 1.5 h,diluted with dichloromethane (40 mL) and quenched with water (30 mL).The aqueous layer was extracted with dichloromethane and the combinedorganics were washed with water and brine, dried over sodium sulphateand concentrated under reduced pressure to furnish the title compound asa brown solid. The crude material was used in the next reaction withoutfurther purification.

ESI/APCI(+): 457 (M+H). EXAMPLE 239

Preparation of Intermediate Methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate

To a cooled (0° C.), stirred solution of methanol (42 ml) under an argonatmosphere was added dropwise sulfuric acid (8 mL). The solution waswarmed to room temperature and used immediately to dissolve2-(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)-2-trimethylsilyloxy)acetonitrile(8.46 g; 3.86 mmol). The resulting mixture was heated at reflux for 24h. After cooling, the volatiles were removed under reduced pressure, theremaining residue was partitioned between ethyl acetate and a saturatedsolution of sodium bicarbonate. The phases were separated and theaqueous layer was extracted with ethyl acetate. The combined organicswere washed with brine, dried over magnesium sulphate and concentratedunder reduced pressure. Purification by flash-chromatography on silicagel using a gradient of ethylacetate (10-80%) in heptane furnished 2.1 g(49%) of the title compound as a light brown solid.

ESI/APCI(+): 418 (M+H).

Example 240 Preparation of Intermediate Methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-hydroxyacetate(2.1 g; 5.03 mmol) in tert-butyl acetate (15 mL; 112 mmol) under anitrogen atmosphere was added perchloric acid 70% (0.342 mL; 5.52 mmol).The reaction was stirred at room temperature for 3 days and quenched byadding a saturated solution of sodium bicarbonate. The mixture wasdiluted with dichloromethane and the phases were separated. The organiclayer was dried over sodium sulphate and concentrated under reducedpressure. Purification by flash-chromatography on silica gel using agradient of ethylacetate (1-40%) in heptane furnished 0.776 g (32%) ofthe title compound as a solid.

ESI/APCI(+): 474 (M+H).

Example 241 Preparation of Methyl2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.050 g; 0.106 mmol) in a mixture of DME-water (3:1) (0.480 mL) wereadded potassium carbonate (0.044 g; 0.317 mmol),tetrakis(triphenylphosphine)palladium(0) (0.012 g; 0.010 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.046g; 0.211 mmol). The solution was stirred for 30 min at 140° C. under amicrowave irradiation. Ethyl acetate was added to the reaction mixtureand the solution was washed with brine. The organic phase was dried overmagnesium sulphate, filtered and concentrated under reduced pressure.Purification by flash chromatography on silica gel using a gradient ofethylacetate (10-80%) in heptane furnished 0.025 g (54%) of the titlecompound as a light yellow oil.

ESI/APCI(+): 439 (M+H).

Example 242 Preparation of2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.035 g; 0.080 mmol) in methanol (1 mL) was added a solution of sodiumhydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated at 60° C.for 18 h. The volatiles were removed under reduced pressure and theresidue was dissolved in water. The mixture was then acidified by adding1N HCl until a precipitate was formed. The solid was filtered, washedwith water and dried under reduced pressure. The crude product wassuspended in a mixture of acetonitrile and methanol, filtered, washedwith acetonitrile and dried under reduced pressure to furnish 0.007 g(20%) of the title compound as a white solid.

ESI/APCI(+): 425 (M+H).

Example 243 Preparation of Methyl2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.100 g; 0.262 mmol) in a mixture of DME-water (3:1) (0.480 mL) wereadded potassium carbonate (0.109 g; 0.786 mmol),tetrakis(triphenylphosphine)palladium(0) (0.030 g; 0.026 mmol) and6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.137g; 0.524 mmol). The solution was stirred for 30 min at 140° C. under amicrowave irradiation. Ethyl acetate was added to the reaction mixtureand the solution was washed with brine. The organic phase was dried overmagnesium sulphate, filtered and concentrated under reduced pressure.Purification by flash chromatography on silica gel using a gradient ofethylacetate (5-80%) in heptane furnished 0.024 g (18%) of the titlecompound as a light yellow oil.

ESI/APCI(+): 481 (M+H).

Example 244 Preparation of2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

Methyl2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.024 g; 0.050 mmol), lithium iodide (0.020 g; 0.150 mmol) and pyridine(0.300 mL) were mixed in a tube, purged with nitrogen, and sealed. Afterheating at 125° C. for 48 h, the solvent was removed under reducedpressure. The residue was dissolved in water and acidified by adding asolution of hydrochloric acid 2N until a precipitate was formed. Thesolid was filtered, washed with water and dried under reduced pressure.Purification by preparative HPLC (HPLC method 1) furnished 0.008 g (34%)of the title compound as a white solid.

ESI/APCI(+): 467 (M+H).

Example 245 Preparation of Intermediate2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid Step 1:

Acetone-1,3-dicarboxylic acid (30 g; 205 mmol) was added in portions toacetic anhydride (55 ml; 582 mmol) and the mixture was stirred at 35° C.for 24 h. The reaction mixture was diluted with toluene (200 ml) andkept at 4° C. for 3 h. A precipitate was isolated by filtration, washedwith toluene and dried under reduced pressure to furnish 18.91 g (54%)of 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate as a light brown solid.

ESI/APCI(−): 169 (M−H).

NMR (¹H, DMSO-d₆) δ 6.35 (1H, s, CH); 3.69 (2H, s, CH₂); 2.30 (s, 3H,CH₃).

Step 2:

A mixture of 1-bromo-4-methoxy-2-nitrobenzene (10 g; 43.1 mmol), ethanol(100 ml), acetic acid (100 ml) and iron powder (9.63 g; 172 mmol) washeated at 100° C. for 2 h. The mixture was cooled to room temperatureand diluted with water (300 ml). The suspension was neutralized withsolid potassium carbonate. The mixture was filtered on a plug of celiteand extracted with dichloromethane. The combined organic layers weredried over magnesium sulphate and concentrated under reduced pressure toafford 2-bromo-5-methoxyaniline, which was used in the next step withoutfurther purification.

NMR (¹H, DMSO-d₆) δ 7.27 (d, J=8.6 Hz, 1H, Harom.); 6.32 (d, J=2.7 Hz,1H, Harom.); 6.22 (dd, J₁=8.7 Hz, J₂=2.8 Hz, 1 H, Harom.); 4.07 (bs, 2H,NH₂); 3.74 (s, 3H, OCH₃).

Step 3:

2-bromo-5-methoxyaniline (6 g; 29.7 mmol) was dissolved in acetic acid(33.7 ml) and 2,6-dioxo-3,6-dihydro-2H-pyran-4-yl acetate (4.59 g; 27.0mmol) was added. The reaction was stirred at 35° C. in a sand bath for 2h. The reaction was quenched by adding ice-water (250 ml), theprecipitate formed was filtered, washed with water and dried overphosphorus pentoxide under reduced pressure to afford 8.98 g (71%) of1-(2-bromo-5-methoxyphenylamino)-1,5-dioxohex-3-en-3-yl acetate as agrey solid.

ESI/APCI(+): 372-374 (M+H).

Step 4:

1-(2-bromo-5-methoxyphenylamino)-1,5-dioxohex-3-en-3-yl acetate (8 g;21.50 mmol) was added in small portions to concentrated sulfuric acid(30 ml) at room temperature and the mixture was stirred for 30 min. Icewas added to the reaction mixture and the formed precipitate wasfiltered, washed with water and dried over phosphorus pentoxide underreduced pressure to afford 5.97 g (89%) of2-(8-bromo-5-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acetic acid as agrey solid.

NMR (¹H, DMSO-d₆) δ 7.76 (d, J=8.8 Hz, 1H, Harom.); 6.77 (d, J=8.9 Hz,1H, Harom.); 6.45 (s, 1H, COCH); 3.88 (s, 2H, CH₂); 3.80 (s, 3H, OCH₃).

Step 5:

To a well-stirred and cold solution of2-(8-bromo-5-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acetic acid (5.5 g;17.62 mmol) in dry THF (90 ml) was slowly added a borane solution (1M inTHF) (38.8 ml; 38.8 mmol) under nitrogen atmosphere. The reaction wasallowed to warm to room temperature and stirred for 24 h. The reactionmixture was carefully quenched with a solution of sodium hydroxide 1N(40 ml), the organic volatiles were removed under reduced pressure andthe remaining aqueous layer was extracted with ethyl acetate. Thecombined organic layers were dried over magnesium sulphate, filtered andconcentrated under reduced pressure to furnish 2.7 g (51%) of8-bromo-4-(2-hydroxyethyl)-5-methoxyquinolin-2(1H)-one as a light brownsolid.

NMR (¹H, DMSO-d₆) δ 9.87 (s, 1H, NH); 7.76 (d, J=8.8 Hz, 1H, Harom.);6,79 (d, J=8.9 Hz, 1H, Harom.); 6.34 (s, 1H, COCH); 4.63 (t, J=5.6 Hz,1H, OH), 3.89 (s, 3H, OCH₃); 3.64 (dt, =J₂=5.9 Hz, 2H, CH₂); 3.14 (t,J=6.3 Hz, 2H, CH₂).

Step 6:

To a stirred solution of8-bromo-4-(2-hydroxyethyl)-5-methoxyquinolin-2(1H)-one (2.7 g; 9.06mmol) at −78° C. was added a solution of boron tribromide (1M in DCM)(55 ml; 55 mmol) dropwise. After 1 h the reaction mixture was allowed towarm up to room temperature and the stirring was carried out for 20 h.The reaction mixture was mixed with ice and water, the solid formed wasisolated by filtration and dried over phosphorus pentoxide under reducedpressure to afford 1.56 g (45%) of8-bromo-5-hydroxy-4-(2-hydroxyethyl)quinolin-2(1H)-one. The crude solidwas used in the next step without further purification.

Step 7:

To a stirred solution of8-bromo-5-hydroxy-4-(2-hydroxyethyl)quinolin-2(1H)-one (0.560 g; 1.971mmol) in tetrahydrofuran (25 ml) was added triphenylphosphine (0.775 g;2.96 mmol) followed by the dropwise addition of diisopropylazodicarboxylate (0.582 ml; 2.96 mmol). The reaction mixture was stirredat room temperature for 2 h, concentrated under reduced pressure and theremaining crude residue was slowly added to phosphorus oxychloride (2.5ml; 26.7 mmol) at room temperature. The reaction mixture was heated at100° C. for 1 h and then cooled to room temperature before removing ofthe volatiles under reduced pressure. The residue was dissolved indichloromethane, washed with a solution of sodium hydroxide 1N, waterand brine, dried over magnesium sulphate and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethyl acetate (5-40%) in heptane furnished 0.220 g (39%) of7-bromo-5-chloro-2,3-dihydropyrano[4,3,2-de]quinoline as a white solid.

ESI/APCI(+): 284-286 (M+H).

Step 8:

To a solution of 7-bromo-5-chloro-2,3-dihydropyrano[4,3,2-de]quinoline(0.220 g; 0.773 mmol) in trifluoroacetic acid (7.5 ml) was added zincdust (0.253 g; 3.87 mmol) and the reaction was stirred at roomtemperature for 16 h. The suspension was filtered, concentrated underreduced pressure, diluted with a solution of sodium hydroxide 1N andextracted with dichloromethane. The organic layer was washed with waterand brine, dried over magnesium sulphate and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethyl acetate (5-80%) in heptane furnished 0.047 g (24%) of7-bromo-2,3-dihydropyrano[4,3,2-de]quinoline as a white solid.

ESI/APCI(+): 250-252 (M+H).

Step 9:

7-bromo-2.3-dihydropyrano[4.3.2-de]quinoline (0.170 g; 0.680 mmol),bis(pinacolato)diboron (0.207 g; 0.816 mmol), anhydrous potassiumacetate (0.133 g; 1.36 mmol) and bis(tricyclohexylphosphine)palladium(0)(0.045 g; 0.068 mmol) in anhydrous 1.4-dioxane (3.1 mL) were mixed in atube, purged with argon and sealed. After heating at 95° C. for 16 h,the mixture was cooled at room temperature, concentrated under reducedpressure and store at 3° C. for 21 h. The brown residue was dissolved inacetonitrile, filtered, and the dark brown solution was concentratedunder reduced pressure. Purification by preparative HPLC (HPLC method 1)furnished 0.044 g (25%) of the title compound as an amorphous solid.

Example 246 Preparation of Methyl2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.065 g; 0.136 mmol) in a mixture of DME-water (3:1) (0.480 mL) wereadded potassium carbonate (0.057 g; 0.409 mmol),tetrakis(triphenylphosphine)palladium(0) (0.016 g; 0.014 mmol) and2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid (0.044 g; 0.205mmol). The solution was stirred for 30 min at 140° C. under a microwaveirradiation. Ethyl acetate was added to the reaction mixture and thesolution was washed with brine. The organic phase was dried overmagnesium sulphate, filtered and concentrated under reduced pressure.Purification by flash chromatography on silica gel using a gradient ofethylacetate (5-80%) in heptane furnished 0.048 g (68%) of the titlecompound as a light yellow oil.

ESI/APCI(+): 517 (M+H).

Example 247 Preparation of2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.040 g; 0.077 mmol) in methanol (1 mL) was added a solution of sodiumhydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated at 60° C.for 18 h. The volatiles were removed under reduced pressure and theresidue was dissolved in water, the mixture was then acidified by adding1N HCl until a precipitate was formed. The solid was filtered, washedwith water and dried under reduced pressure. Purification by preparativeHPLC (HPLC method 1) furnished 0.005 g (12%) of the title compound as awhite solid.

ESI/APCI(+): 503 (M+H).

Example 248 Preparation of Intermediate2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1:

To a solution of 2-fluoro-5-methylphenol (5 g; 39.6 mmol) and allylbromide (5.48 ml; 63.4 mmol) in DMF (200 ml) under a nitrogen atmosphereat room temperature was added sodium hydride (60% in oil) (3.33 g; 83mmol) in small portions. The reaction was stirred at room temperaturefor 21 h, then diluted with ethyl acetate (500 ml) and washed with water(3×500 ml). The organic layer was dried over magnesium sulphate,filtered and concentrated under reduced pressure. The expected compoundwas used in the next reaction without further purification.

Step 2:

2-(allyloxy)-1-fluoro-4-methylbenzene (7 g; 42.1 mmol) was placed in amicrowave oven and irradiated at 240° C. for 20 min. The resulting blackresidue was used in the next reaction without further purification.

Step 3:

To a cold (0° C.) solution of 2-allyl-6-fluoro-3-methylphenol (1 g; 6.02mmol) in dry tetrahydrofuran (39 ml) was added a borane solution (1M inTHF, 12 ml; 12 mmol) dropwise. The reaction mixture was allowed to warmto room temperature and stirred for 2.5 h. The reaction mixture was thencooled to 0° C. and carefully treated with a solution of sodiumhydroxide 6 N (20 ml) followed by a slow addition of hydrogen peroxide(12.3 ml; 120.3 mmol). The resulting mixture was allowed to warm to roomtemperature and stirred for 1 h. The reaction mixture was diluted with asolution of hydrochloric acid 10% (10 ml) and extracted with ethylacetate. The combined organic layers were dried over magnesium sulphate,filtered and concentrated under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of ethyl acetate(10-80%) in heptane furnished 0.864 g (78%) of the expected compound.

ESI/APCI(+): 185 (M+H).

NMR (¹H, DMSO-d₆) δ 6.85 (1H, dd, J₁=8.1 Hz, J₂=10.9, Harom.); 6.55 (1H,dd, J₁=5.2 Hz, J₂=8.1 Hz, Harom.); 3.42 (2H, t, J=6.03 Hz, CH₂); 2.59(2H, t, 7.9, CH₂); 2.19 (3H, s, CH₃); 1.57 (m, 2H, CH₂).

Step 4:

To a solution of 6-fluoro-2-(3-hydroxypropyl)-3-methylphenol (0.600 g;3.26 mmol) in tetrahydrofuran (46 ml), triphenylphosphine (1.11 g; 4.23mmol) and diisopropyl azodicarboxylate (0.834 ml; 4.23 mmol) were addedand the solution was stirred at room temperature for 2 h. The volatileswere removed under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of ethyl acetate(5-40%) in heptane furnished 0.470 g (87%) of the expected compound.

ESI/APCI(+): 167 (M+H).

Step 5:

To a solution of 8-fluoro-5-methylchroman (0.300 g; 1.81 mmol) in aceticacid (4.4 mL) was added a solution of bromine (0.185 mL; 3.61 mmol)) inacetic acid (2.5 mL). The reaction mixture was stirred for 15 min atroom temperature and then diluted with toluene and concentrated underreduced pressure. Ethyl acetate was added and the solution was washedwith a saturated solution of sodium thiosulphate and a saturatedsolution of sodium hydrogen carbonate. The organic layers were combined,dried over magnesium sulphate and concentrated under reduced pressure.Purification by flash-chromatography on silica gel using a gradient ofethyl acetate (5-40%) in heptane furnished 0.305 g (69%) of the expectedcompound.

ESI/APCI(+): 245-247 (M+H).

NMR (¹H, DMSO-d6) δ 7.34 (1H, d, J=10.5 Hz); 4.13 (2H, t, J=5.1 Hz,);2.70 (2H, t, J=6.03 Hz); 2.20 (3H, s); 1.90 (2H, m).

Step 6:

6-bromo-8-fluoro-5-methylchroman (0.200 g; 0.816 mmol),bis(pinacolato)diboron (0.414 g; 1.63 mmol), anhydrous potassium acetate(0.280 g; 2.86 mmol) and[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.067 g;0.082 mmol) in anhydrous DMF (9.4 mL) were mixed in a tube, purged withargon, and sealed. After heating at 95° C. for 16 h, the reactionmixture was cooled to room temperature, diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with water,dried over magnesium sulphate, filtered and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethyl acetate (5-100%) in heptane furnished 0.216 g (91%) ofthe title compound.

NMR (¹H, DMSO-d₆) δ 7.15 (1H, d, J=12 Hz, Harom.); 4.15 (2H, t, J=5.1Hz, OCH₂); 2.60 (2H, t, J=6 Hz, O(CH₂)₂CH₂); 2.12 (3H, s, CH₃); 1.96(2H, m, OCH₂CH₂); 1.28 ′6H, s, 4×CH₃).

Example 249 Preparation of Methyl2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.075 g; 0.158 mmol) in a mixture of DME-water (3:1) (0.480 mL) wereadded potassium carbonate (0.066 g; 0.475 mmol),tetrakis(triphenylphosphine)palladium(0) (0.018 g; 0.016 mmol) and2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.069 g; 0.238 mmol). The solution was stirred for 30 min at 140° C.under a microwave irradiation. Ethyl acetate was added to the reactionmixture and the solution was washed with brine. The organic phase wasdried over magnesium sulphate, filtered and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethylacetate (0-40%) in heptane furnished 0.046 g (57%) ofthe title compound as a light yellow oil.

ESI/APCI(+): 512 (M+H).

Example 250 Preparation of2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.046 g; 0.090 mmol) in methanol (1.1 mL) was added a solution ofsodium hydroxide 10 N (0.110 mL; 1.1 mmol) and the mixture was heated at60° C. for 18 h. The volatiles were removed under reduced pressure andthe residue was dissolved in water, the mixture was then acidified byadding 1N HCl until a precipitate was formed. The solid was filtered,washed with water and dried under reduced pressure. Purification bypreparative HPLC (HPLC method 1) furnished 0.005 g (12%) of the titlecompound as a white solid.

ESI/APCI(−): 496 (M−H).

ESI/APCI(+): 498 (M+H).

Example 251 Preparation of Intermediate2-[5-chlorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1:

To a solution of 3-chlorophenol (10 g; 78 mmol) in dry tetrahydrofuran(78 ml) under a nitrogen atmosphere was added sodium hydride (60% inoil) (6.22 g; 156 mmol) in small portions. The reaction was stirred atroom temperature for 1 h and diethylcarbamic chloride (19.71 ml; 156mmol) was slowly added and the reaction was stirred at room temperaturefor 21 h. The reaction was quenched with water, concentrated underreduced pressure, extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over magnesium sulphate, filteredand concentrated under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of ethyl acetate(0-40%) in heptane furnished 9.86 g (56%) of 3-chlorophenyldiethylcarbamate.

ESI/APCI(+): 228 (M+H).

NMR (¹H, DMSO-d₆) δ 7.41 (m, 1H, Harom.); 7.31-7.27 (m, 2H, Harom.);7.13-7.01 (m, 1H, Harom.); 3.48-3.13 (m, 4H, 2×CH₂); 1.21-1.09 (m, 6H,2×CH₃).

Step 2:

To a solution of lithium diisopropylamine (2M in THF) (21.40 ml; 42.8mmol) in dry tetrahydrofuran (117 ml) under nitrogen atmosphere at −78°C. was added 3-chlorophenyl diethylcarbamate (8.86 g; 38.91 mmol). Thereaction mixture was stirred for 30 min at −78° C., and iodine (0.669 g;46.7 mmol) was added. The solution was stirred for 30 min. at 0° C. andwas then allowed to warm up to room temperature for 2 h. The reactionmixture was quenched by adding water and the organics were removed underreduced pressure. The aqueous phase was extracted with ethyl acetate,washed with a solution of hydrochloric acid 1 N, dried over magnesiumsulphate, filtered and concentrated under reduced pressure to afford8.32 g (55%) of 3-chloro-2-iodophenyl diethylcarbamate as brown solid.

NMR (¹H, DMSO-d₆) δ 7.47-7.38 (m, 2H, 2 Harom.); 7.13 (dd, J=7.44 Hz,1.92 Hz, 1H, Harom.); 3.47 (q, J=7.2 Hz, 2H, CH₂); 3.37 (q, J=7.2 Hz,2H, CH₂); 1.28 (t, J=7.2 Hz, 3H, CH₃); 1.14 (t, J=7.2 Hz, 3H, CH₃).

Step 3:

3-chloro-2-iodophenyl diethylcarbamate (2.70 g; 7.64 mmol, propargylalcohol (0.902 mL, 15.27 mmol), tetrakistriphenylphosphine (0.882 g;0.764 μmol), copper iodide (0.292 g; 1.53 mmol), diisopropylamine (1.51mL; 10.69 mmol) were mixed in a tube, purged with argon, and sealed.After heating at 100° C. for 1 h, the reaction mixture was cooled downto room temperature. The reaction mixture was poured into ethyl acetate(27 ml) and washed with a solution of hydrochloric acid 10%, dried overmagnesium sulphate, filtered and concentrated under reduced pressure.Purification by flash-chromatography on silica gel using a gradient ofethyl acetate (10-100%) in heptane furnished 0.69 g (17%) of the desired3-chloro-N,N-diethyl-2-(3-hydroxyprop-1-ynyl)benzamide.

NMR (¹H, DMSO-d₆) δ 7.44-7.37 (m, 2H, 2 Harom.); 7.13 (dd, J=7.08 Hz,2.19 Hz, 1H, Harom.); 5.41 (t, J=5.98 Hz, 1H, OH); 4.32 (d, J=5.98 Hz,2H, OCH₂); 3.42 (q, J=6.9 Hz, 2H, CH₂); 3.29 (q, J=6.9 Hz, 2H, CH₂);1.23 (t, J=6.9 Hz, 3H, CH₃); 1.12 (t, J=6.9 Hz, 3H, CH₃).

Step 4

To a solution of 3-chloro-N,N-diethyl-2-(3-hydroxyprop-1-ynyl)benzamide(0.690 g; 2.45 mmol) in ethyl acetate (15.4 ml) was added Rh—Al₂O₃(0.655 g; 0.318 mmol). The flask was purged with nitrogen and saturatedunder hydrogen atmosphere. The reaction was stirred at room temperaturefor 21 h, then filtered on a plug of celite and concentrated underreduced pressure. Purification by flash chromatography on silica gelusing a gradient of ethyl acetate (10-80%) in heptane furnished 0.411 g(33%) of the desired 3-chloro-2-(3-hydroxypropyl)phenyldiethylcarbamate.

Step 5:

To a solution of the 3-chloro-2-(3-hydroxypropyl)phenyl diethylcarbamate(0.410 g; 1.43 mmol) in ethanol (14.5 ml) was added solid sodiumhydroxide (0.144 g; 3.59 mmol) and the reaction mixture was heated atreflux for 21 h. After cooling, the volatiles were removed under reducedpressure, water was added and the mixture was extracted with diethylether, the combined organics were dried over magnesium sulphate,filtered and concentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (15-100%)in heptane furnished 0.57 g (79%) of the desired3-chloro-2-(3-hydroxypropyl)phenol.

Step 6:

To a solution of 3-chloro-2-(3-hydroxypropyl)phenol (0.56 g; 3 mmol) andtriphenylphosphine (1.02 g; 3.90 mmol) in tetrahydrofuran (42 mL) wasadded diisopropyl azadicarboxylate (0.766 mL; 3.90 mmol), the reactionmixture was stirred at room temperature for 4 h and the volatiles wereremoved under reduced pressure. Purification by flash chromatography onsilica gel using a gradient of ethyl acetate (5-80%) in heptanefurnished 0.121 g (24%) of 5-chlorochroman.

NMR (¹H, DMSO-d₆) δ 7.09 (1H, Harom.); 6.96 (1H, Harom.); 6.73 (1H,Harom.); 4.11 (2H, t, J=5.1 Hz, OCH₂); 2.70 (2H, t, J=6.3 Hz,O(CH₂)₂CH₂); 1.94 (2H, m, OCH₂CH₂).

Step 7:

To a solution of 5-chlorochroman (0.101 g; 0.6 mmol) and silver nitrate(0.112 g; 0.66 mmol) in methanol (6 mL) was added iodine (0.153 g; 0.6mmol) and the reaction mixture for 30 min. The reaction was quenched byadding a solution of sodium thiosulphate 0.5M (2.5 mL) and the aqueouslayer was extracted with ethyl acetate. The organics were combined,dried over sodium sulphate, filtered and concentrated under reducedpressure. Purification by flash chromatography on silica gel using agradient of ethyl acetate (5-80%) in heptane furnished 0.088 g (50%) of5-chloro-4-iodochroman.

Step 8:

5-chloro-4-iodochroman (0.082 g; 0.27 mmol), bis(pinacolato)diboron(0.137 g; 0.54 mmol), anhydrous potassium acetate (0.093 g; 0.946 mmol)and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.021g; 0.027 mmol) in anhydrous DMF (2.7 mL) were mixed in a tube, purgedwith argon, and sealed. The reaction mixture was heated at 95° C. for 18h, cooled at room temperature, diluted with water and extracted withethyl acetate. The combined organic layers were washed with a saturatedsolution of sodium chloride, water, dried over magnesium sulphate,filtered and concentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (5-100%)in heptane furnished 0.016 g (20%) of the title compound.

Example 252 Preparation of Methyl2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

To a solution of methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.075 g; 0.158 mmol) in a mixture of DME-water (3:1) (0.480 mL) wereadded potassium carbonate (0.066 g; 0.475 mmol),tetrakis(triphenylphosphine) palladium(0) (0.018 g; 0.016 mmol) and2-(5-chlorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.070g; 0.238 mmol). The solution was stirred for 30 min at 140° C. undermicrowave irradiation. Ethyl acetate was added to the reaction mixtureand the solution was washed with brine. The organic phase was dried overmagnesium sulphate, filtered and concentrated under reduced pressure.Purification by flash chromatography on silica gel using a gradient ofethyl acetate (0-40%) in heptane furnished 0.027 g (34%) of the titlecompound as a light yellow oil.

ESI/APCI(+): 514-516 (M+H).

Example 253 Preparation of2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of Methyl2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.027 g; 0.053 mmol) in methanol (0.9 mL) was added a solution ofsodium hydroxide 10 N (0.090 mL; 0.90 mmol) and the mixture was heatedto 60° C. for 18 h. The volatiles were removed under reduced pressureand the residue was dissolved in water, the mixture was then acidifiedby adding 1N HCl until a precipitate was formed. The solid was filtered,washed with water and dried under reduced pressure. Purification bypreparative HPLC (HPLC method 1) furnished 0.005 g (18%) of the titlecompound as a white solid.

ESI/APCI(+): 500-502 (M+H).

Example 254 Preparation of Intermediate[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]bromomethane

To a solution of(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methanol(0.323 g; 1 mmol) in dry dichloromethane (5 mL) were addedtriphenylphosphine (0.314 g; 1.2 mmol) and carbon tetrabromide (0.431 g;1.3 mmol). The resulting solution was stirred for 21 h. The volatileswere removed under reduced pressure and the remaining residue waspurified by flash chromatography on silica gel using a gradient of ethylacetate (1-30%) in heptane to afford 0.310 g (80%) of the title compoundas a white solid.

ESI/APCI(+): 387-389 (M+H).

Example 255 Preparation of Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]methylphosphonate

A solution of(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)bromomethane(0.309 g; 0.8 mmol) in trimethylphosphite (8 mL) was heated at refluxfor 18 h. The volatiles were removed under reduced pressure and theremaining residue was used in the next step without furtherpurification.

ESI/APCI(+): 416 (M+H).

Example 256 Preparation of Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]butylphosphonate

To a solution of dimethyl(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)methylphosphonate(0.332 g; 0.8 mmol) in dry DMF (3.2 mL) at −10° C. was added LHMDS (1Min THF) (0.880 mL; 0.880 mmol) and 1-propyliodide (0.117 mL; 1.2 mmol).The reaction mixture was allowed to warm up to room temperature and thereaction mixture was stirred for 18 h. A saturated solution of ammoniumchloride (4 ml) was added and the mixture was extracted with ethylacetate. The organics were combined, washed with brine, dried overmagnesium sulphate and concentrated under reduced pressure. Purificationby flash chromatography on silica gel using a gradient of ethyl acetate(1-40%) in dichloromethane furnished 0.354 g (96%) of the title compoundas a light yellow oil.

ESI/APCI(+): 458 (M+H).

Example 257 Preparation of1-(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl)butylphosphonicacid

To a cold solution of dimethyl(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butylphosphonate(0.351 g; 0.767 mmol) in dry DMF (4 mL) and protected by an aluminiumfoil was added 2,6-lutidine (0.444 mL; 3.84 mmol) and then, very slowly,trimethylsilyl iodide (3.59 mL; 15.34 mmol). The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture was quenchedby adding a saturated solution of ammonium chloride. The aqueous layerwas extracted with ethyl acetate, the organics were combined, dried oversodium sulphate and concentrated under reduced pressure. Acetonitrilewas added to the organic residue and a white precipitate was filtered,washed and the filtrate was concentrated under reduced pressure. Theresidue was dissolved in a mixture methanol-acetonitrile (1:1, 6 mL) anda solution of ammonium acetate 10 mM (2 mL) was added. After 20 min, aprecipitate was formed, filtered, washed with a small amount ofacetonitrile. The solid was partitioned between ethyl acetate and HCl 1Nand the organic layer was dried over sodium sulphate, filtered andevaporated under reduced pressure to provide 0.034 g (10%) of the titlecompound as an ochre solid.

ESI/APCI(+): 430 (M+H).

Example 258 Preparation of Methyl2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

Methyl2-[4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.050 g; 0.106 mmol), thiophenol (0.013 mL; 0.127 mmol), triethylamine(0.030 mL; 0.211 mmol) and tetrahydrofuran (0.211 mL) were mixed in atube, purged with nitrogen, and sealed. After heating at 100° C. for 18h, the mixture was cooled down and diluted with dichloromethane andwashed with water. The organic layer was dried over sodium sulphate,filtered and concentrated under reduced pressure. Purification by flashchromatography on silica gel using a gradient of ethyl acetate (1-30%)in heptane furnished 0.032 g (56%) of the title compound as a colorlessoil.

ESI/APCI(+): 456 (M+H).

Example 259 Preparation of2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(0.032 g; 0.070 mmol) in methanol (1 mL) was added a solution of sodiumhydroxide 10 N (0.100 mL; 1 mmol) and the mixture was heated at 65° C.for 18 h. After cooling, the organic volatiles were removed underreduced pressure and the aqueous phase was then acidified with asolution of hydrochloric acid 2N until a precipitate was formed. Thesolid was filtered, washed with water and dried under reduced pressureto afford 0.017 g (50%) of the title compound as a white solid.

ESI/APCI(+): 442 (M+H).

Example 260 Preparation of Intermediate(6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone

To a solution of 3-oxo-3-p-tolylpropanenitrile (1.59 g; 10 mmol) in dryethanol (10 mL) were added 1-acetylpiperidin-4-one (2.12 g; 15 mmol),morpholine (1.32 mL; 15 mmol) and sulfur (0.480 g; 15 mmol). Thereaction mixture was stirred at room temperature for 18 h under anitrogen atmosphere. The volatiles were removed under reduced pressureand purification by flash-chromatography on silica gel using a gradientof ethyl acetate (2-100%) in dichloromethane as eluent furnished 2.6 g(82%) of the title compound as a bright yellow solid.

ESI/APCI(+): 315 (M+H).

Example 261 Preparation of Ethyl[7-acetyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate

To a solution of(6-acetyl-2-amino-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-3-yl)(p-tolyl)methanone(2 g; 6.36 mmol) and ethyl 4-oxo-2-propylpentanoate (1.3 g; 7 mmol) indry DMF (25 mL) under nitrogen atmosphere was addedchlorotrimethylsilane (3.25 mL; 25.45 mmol). The mixture was stirred ina sealed tube and heated at 100° C. for 48 h. After cooling, water (25mL) was added and the resulting mixture was extracted with ethylacetate. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure. Purification byflash-chromatography on silica gel using a gradient of methanol (0-20%)in dichloromethane furnished 2.79 g (94%) of the title compound.

ESI/APCI(+): 465 (M+H).

Example 262 Preparation of[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoateammonium salt

To a suspension of ethyl[7-acetyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate(2.79 g; 6 mmol) in a mixture methanol-ethanol (2:1) (141 mL) was addeda solution of 5% sodium hydroxide (144 mL; 180 mmol) and the reactionmixture was heated at 90° C. for 18 h. The organic volatiles wereremoved under reduced pressure and the remaining basic solution wasacidified with a solution of hydrochloric acid 1N until pH 2. The beigeprecipitate was filtered and dried under reduced pressure. Purificationby preparative HPLC (HPLC method 3) furnished 0.84 g (34%) of the titlecompound as a yellow solid.

ESI/APCI(+): 395 (M+H).

Example 263 Preparation of[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,6-diaza-fluoren-3-yl]pentanoateammonium salt and Example 264 Preparation of[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,8-diaza-fluoren-3-yl]pentanoateammonium salt Step 1:

To a solution of 3-oxo-3-p-tolylpropanenitrile (0.795 g; 5 mmol) in dryethanol (5 mL) were added N-Boc piperidin-3-one (1.49 g; 7.5 mmol),morpholine (0.660 mL; 7.5 mmol) and sulfur (0.240 g; 7.5 mmol). Thestirred reaction mixture was stirred at room temperature for 48 h undera nitrogen atmosphere and then heated at 60° C. for 18 h. The volatileswere removed under reduced pressure and the remaining crude was purifiedby flash chromatography on silica gel using a gradient of ethyl acetate(1-50%) in dichloromethane to afford 0.981 g (52%) of a yellow oil.

ESI/APCI(+): 373 (M+H).

Step 2:

The compound from step 1 (0.968 g; 2.6 mmol) and ethyl 4-oxohexanoate(0.726 g; 3.9 mmol) were mixed in DMF (10 mL) under nitrogen atmosphereand chlorotrimethylsilane (1.33 mL; 10.4 mmol) was added dropwise. Themixture was stirred in a sealed tube and heated to 100° C. for 24 h.After cooling, the mixture was poured in water and the volatiles wereremoved under reduced pressure. Purification by flash chromatography onsilica gel column using a gradient of methanol (1-20%) indichloromethane furnished 0.582 g (53%) of a brown oil.

ESI/APCI(+): 423 (M+H).

Step 3:

To a suspension of product from step 2 (0.582 g; 1.38 mmol) in a mixturemethanol-ethanol (2:1) (42 mL) was added a solution of sodium hydroxide5% (33 mL; 41.32 mmol) and the reaction mixture was heated at 90° C. for5 h. The organic volatiles were removed under reduced pressure and theremaining basic solution was washed with a solution of hydrochloric acid1N until pH 2. The beige precipitate was filtered and dried underreduced pressure. Purification by preparative HPLC (HPLC method 3)furnished 0.073 g (13%) of a mixture of[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,6-diaza-fluoren-3-yl]pentanoateammonium salt and[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,8-diaza-fluoren-3-yl]pentanoateammonium salt as a yellow solid.

ESI/APCI(+): 395 (M+H).

Example 265 Preparation of Methyl2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate

Phenol (11.93 mg, 0.127 mmol) was placed in a 2 ml biotage tube,dissolved in tetrahydrofuran (300 μl) and sodium hydride (60%, 5.07 mg,0.127 mmol) was added. The tube was purged with nitrogen and sealed.After 10 min. a solution of Methyl2-[4-iodo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(50 mg, 0.106 mmol) in tetrahydrofuran (300 μl) was added dropwise andthe mixture was heated in a sand bath at 100° C. overnight. Aftercooling, the mixture was partitioned between water and dichloromethane,filtered over a phase separator filter (1PS) and concentrated underreduced pressure. The crude material was purified by flashchromatography on silica gel using a gradient of ethyl acetate (5-40%)in heptane to provide 18 mg (39%) of the title compound as an oil.

ESI/APCI(+): 440 (M+H).

Example 266 Preparation of2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

To a solution of methyl2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate18 mg, 0.041 mmol) in methanol (0.5 mL) was added a solution of sodiumhydroxide 10 N (50 μl, 0.500 mmol) and the mixture was heated at 65° C.for 18 h. After cooling, the organic volatiles were removed underreduced pressure and the aqueous phase was then acidified with asolution of hydrochloric acid 2N until a precipitate was formed. Thesolid was filtered, washed with water and dried under reduced pressureto afford 0.006 g (34%) of the title compound as a white solid.

ESI/APCI(+): 425 (M+H).

Example 267 Preparation of2-[2-methyl-4-(phenylamino)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid

Aniline (1 eq) is placed in a 2 ml biotage tube, and is dissolved in dryDMF (300 μl) and sodium hydride (1 eq) is added. The tube is purged withnitrogen, sealed and is heated at 120° C. for 10 min. After cooling, asolution of methyl2-[4-iodo-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate(50 mg, 0.106 mmol) in dry DMF (300 μl) is added dropwise and thereaction mixture is heated at 120° C. overnight. After cooling, themixture is partitioned between water and dichloromethane, filtered overa phase separator filter (1PS) and concentrated under reduced pressure.The crude material is purified by flash chromatography on silica gelusing a gradient of ethyl acetate (5-100%) in heptane to provide thedesired methyl ester compound which is immediately hydrolyzed into the2-[2-methyl-4-(phenylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid following standard hydrolysis conditions known to the skilled inthe art.

It is known to the skilled in the art that many different nucleophiles(e.g. primary amines, secondary amines, alcohols, thiols) may be coupledto carbon atom by displacing a leaving group (LG). Some procedures areset forth in the examples here above or are published in the literature.More detailed information can be found in the following references :Bioorganic & Medicinal Chemistry 15, (2007), 7809-7829; Bioorganic &Medicinal Chemistry 16, (2008), 7671-7690; Bioorganic & MedicinalChemistry 16, (2008), 5890-5898; Bioorganic & Medicinal ChemistryLetters 18, (2008), 2850-2853; Bioorganic & Medicinal Chemistry Letters18, (2008), 4237-4241; Bioorganic & Medicinal Chemistry Letters 18,(2008), 3603-3606; Bioorganic & Medicinal Chemistry Letters 19, (2009),701-705.

Example 268 Preparation of[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid

To a solution of potassium tert-butoxide (0.269 g; 2.4 mmol) in drytert-butanol (10 mL) under a nitrogen atmosphere at 50° C. were added(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(p-tolyl)methanone(0.542 g; 2 mmol) and diethyl succinate (0.464 mL; 2.8 mmol). Themixture was heated at reflux for 24 h and then cooled down to roomtemperature. Water (8 ml) was added and then the reaction mixture wasacidified with a solution of hydrochloric acid 1N until pH 1. Theaqueous layer was extracted with diisopropylether (3×10 ml) and ethylacetate (3×10 mL). The organics were combined and the volatiles wereremoved under reduced pressure. The remaining crude was crystallizedfrom acetic acid to furnish 0.101 g (14%) of the title compound.

ESI/APCI(+): 354 (M+H).

Example 269 Preparation of[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benenzothieno[2,3-b]pyridin-3-yl]aceticacid

To a solution of[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid (1 mmol) in dry methanol (10 mL) was carefully added thionylchloride (0.725 mL; 1.19 mmol) and the mixture was heated at reflux for48 h. After cooling, the volatiles were removed under reduced pressureand the remaining residue was dissolved in ethyl acetate, washed withbrine, dried over sodium sulphate, filtered and concentrated underreduced pressure. Purification by flash chromatography on silica gelusing a gradient of methanol (0-20%) in ethyl acetate furnished 0.352 g(95%) of the title compound as a beige solid.

ESI/APCI(+): 368 (M+H).

Example 270 Preparation of Methyl[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate

The compound is prepared from the[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid following standard esterification procedures known to the skilledin the art. As an example, the transformation is achieved using acatalytic amount of sulphuric acid in methanol.

Example 271 Preparation of Methyl2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate

The compound is prepared from the methyl[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetateand 1-iodopropane as described in the general method C.

Example 272 Preparation of2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

The compound is prepared from the methyl2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoateby standard basic hydrolysis conditions as described in the differentexamples here above.

Example 273 Preparation of2-[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid

The compound is prepared from the methyl2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoatefollowing procedures known to the skilled in the art. As an example, thetransformation is achieved using reagents such as trimethylsilylchloride or iodide (Tetrahedron 2010, 66(1), 102-110; TetrahedronLetters 2001, 42(32), 5359-5361), lithium iodide (WO 2008070908) orboron tribromide (WO 2009035575).

Part B Methodology for Determination of Antiviral and CytostaticActivity Example 274 Evaluation of the Anti-HIV Activity of theCompounds of the Invention

A rapid and automated assay procedure was used for the in vitroevaluation of anti-HIV agents. An HTLV-1 transformed T4-cell line MT-4,which was previously shown to be highly susceptible to and permissivefor HIV infection, served as the target cell line. Inhibition of theHIV-induced cytopathogenic effect was used as the end point. Theviabitlity of both HIV-and mock-infected cells was assessedspectrophotometrically via in situ reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The50% cytotoxic concentration (CC50 in μM or μg/ml) was defined as theconcentration of compound that reduced the absorbance of themock-infected control sample by 50%. The percent protection achieved bythe compound in HIV-infected cells was calculated by the followingformula:

$\frac{\left( {OD}_{T} \right)_{HIV} - \left( {OD}_{C} \right)_{HIV}}{\left( {OD}_{C} \right)_{MOCK} - \left( {OD}_{C} \right)_{HIV}}\mspace{14mu} {expressed}\mspace{14mu} {in}\mspace{14mu} \%$

whereby (OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% inhibitory concentration (EC50 inμM or μg/ml). The ratio of CC₅₀ to EC₅₀ was defined as the selectivityindex (SI). Examples of EC₅₀, CC₅₀ and SI values for inhibition ofproliferation of HIV by particular compounds of the invention are listedin table 2 herein below. Examples of inhibition of cell proliferation byparticular compounds of the invention can be found by looking at therespective CC₅₀ values in the MT-4 cell line.

-   Cells: MT-4 cells (Miyoshi et al., 1982) were grown and maintained    in RPMI 1640 medium supplemented with 10% heat-inactivated fetal    calf serum, 2 mM I-glutamine, 0.1% sodium bicarbonate, and 20 μg of    gentamicin per ml. Alternatively, the MT-4 cells may also be grown    in RPMI 1640 medium supplemented with 10% FCS and 20 μg/ml of    gentamicin (RPMI-complete).-   Viruses: The HIV-1 (IIIB) strain (Popovic et al., 1984) as well as    the the HIV-1 (NL4.3) strain (Adachi et al., J. Virol. 59, 284-291    (1986)) were used.

REFERENCES

-   Popovic, M, Sarngadharan, M. G., Read, E., Gallo, R. C. (1984),    Science, 224, 497-500-   Barr-Sinoussi, F., Chermann, J. C., Rey, F., Nugeyre, M. T.,    Chamaret, S., Gruest, J., Dauguet, C., Axler-Blin, C., V,zinet-Brun,    F., Rouzioux, C., Rozenbaum, W., Montagnier, L. (1983) Isolation of    a T-lymphotropic retrovirus from patient at risk for AIDS, Science    (Wash DC) 220, 868-871.Miyoshi, I., Taguchi, H., Kobonishi, I.,    Yoshimoto, S., Ohtsuki, Y., Shiraishi, Y. and Akagi, T. (1982) Type    C virus-producing cell lines derived from adult T cell leukemia,    Gann mongr, 28, 219-228.

Example 275 Alphascreen Assay to Measure the LEDGF-Integrase InteractionInhibitory Activity of Compounds of the Invention

The AlphaScreen assay was performed according to the manufacturer'sprotocol (Perkin Elmer, Benelux). Reactions were performed in 25 μlfinal volume in 384-well Optiwell™ microtiter plates (Perkin Elmer). Thereaction buffer contained 25 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mMMgCl₂, 0.01% (v/v) Tween-20 and 0.1% (w/v) bovine serum albumin.His₆-tagged integrase (300 nM final concentration) was incubated withthe compounds for 30 min at 4° C. The compounds were added at varyingconcentrations spanning a wide range from 0.1 up to 100 μM. Afterwards100 nM flag-LEDGF/p75 was added and incubation was prolonged for anadditional hour at 4° C. Subsequently 5 μl of Ni-chelate-coated acceptorbeads and 5 μl anti-flag donor beads were added to a final concentrationof 20 μg/ml of both beads. Proteins and beads were incubated for 1 h at30° C. in order to allow association to occur. Exposure of the reactionto direct light was omitted as much as possible and the emission oflight from the acceptor beads was measured in the EnVision plate reader(Perkin Elmer, Benelux) and analyzed using the EnVision managersoftware. IN/DNA binding was analyzed in a similar setting usingHis₆-tagged integrase (1 μM final concentration) and anoligodeoxynucleotide mimicking the IN ELISA oligonucleotide substrate(30 nM final concentration). Counterscreens with JPO2 or PogZ,respectively, were essentially performed as described previously.

-   Expression and purification of recombinant proteins: His₆-tagged    HIV-1 integrase, 3xflag-tagged LEDGF/p75, MBP-JPO2 and MBP-PogZ were    purified for AlphaScreen applications as described previously    23,25,56.

REFERENCES

-   Bartholomeeusen, K., et al. Differential interaction of HIV-1    integrase and JPO2 with the C terminus of LEDGF/p75. J. Mol. Biol.    372, 407-421 (2007).-   Bartholomeeusen, K., et al. Lens Epithelium Derived Growth    Factor/p75 interacts with the transposase derived DDE domain of    pogZ. J. Biol. Chem. (2009).-   Busschots, K., et al. The interaction of LEDGF/p75 with integrase is    lentivirus-specific and promotes DNA binding. J. Biol. Chem. 280,    17841-17847 (2005).

TABLE 2 Activity of the compounds according to the methods of exmples260 and 261. Cpd Alphascreen EC₅₀ CC₅₀ code IC₅₀ (μM) (μM) (μM) SI 1006.61 1.69 121.15 72 101 55.28 64.1 >125 >2 105 64.34 >62.67 62.67 / 10653.94 96.4 >125 >1 107 34.74 13.16 75.69 8 108 4.48 2.19 57.87 27 1096.81 2.22 57.94 26 110 4.31 0.76 72.16 95 111 ND 1.28 54.39 43 112 1.110.803 67.69 84 113 0.75 0.44 80.6 183 114 <1 0.58 125.5 217 115 17.65.03 131 26 116 0.62 1.21 14.73 12 117 0.78 0.53 54.29 107 11823.38 >50.2 50.2 / 119 2.66 31.57 108.75 4 120 2.72 1.51 101.32 67 1223.2 5.3 79.8 15 124 41.03 >116.85 116.85 / 125 77.01 66.5 >125 >2 12656.28 >30.14 30.14 / 127 2.85 0.79 82.94 105 128 11.34 4.07 121.17 30129 48 >130 130 / 130 30.57 29.6 130 4 131 4.54 2.43 127 52 13244.65 >131 131 / 133 7.8 17.97 165 8 134 84.11 >114 114 / 135 55.7842.39 109 3 136 4.34 1.02 86.35 85 137 51.93 >111 111 / 138 39.93 43.34100 2 139 9.24 5.32 55.05 10 140 18.06 28.2 100 4 141 23.69 14.8 55.5 4142 7.43 4.58 92.2 20 143 49.22 >66 66 / 144 6.64 20 63 3 145 29.6123 >125 >1 146 4.76 2.98 124 42 147 23.71 8.79 41.5 5 148 2.19 0.53 70132 149 74.35 >67 67 / 150 1.37 0.78 38.5 49 151 21.47 8 48 6 153 43.6517 >125 >8 154 8.12 6.28 90.5 14 155 81.89 >22 22 / 156 59.62 >98 98 /157 26.4 >35 35 / 158 13.46 5.48 58.5 11 159 13.31 7.54 99.5 13 16017.74 14.38 74 5 161 0.0554 0.147 157 1061 162 1.57 0.33 71.66 217 1634.5 >23 23 / 165 <1 0.867 89 102 166 3 >131 131 / 167 63.7 >26.1 26.1 /170 0.05 0.0263 116.5 4429 171 1.21 0.1115 130 1166 173 5.9 4.51 225 50175 <1 8.89 79.2 9 177 11.74 1.17 >212 >181 181 8.06 2.89 81 28 182~80 >27.3 27.3 / 184 3.44 0.157 237 1513 186 0.43 0.038 110 2900 18813.67 25.6 105 4 190 0.37 0.015 129 8401

All publications and patent applications cited herein are incorporatedby reference to the same extent as if each individual publication orpatent application was specifically and individually indicated to beincorporated by reference. Specifically cited sections or pages of theabove cited works are incorporated by reference with specificity. Theinvention has been described in detail sufficient to allow one ofordinary skill in the art to make and use the subject matter of thefollowing Embodiments. Many modifications are possible in theembodiments without departing from the teachings thereof. All suchmodifications are intended to be encompassed within the claims of theinvention.

1. A compound according to formula (A),

wherein, R¹ is independently selected from alkyl; alkenyl; alkynyl;cycloalkyl; cycloalkenyl; cycloalkynyl; aryl; heterocycle; arylalkyl;arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; orheterocycle-alkynyl; wherein in the cycloalkyl, cycloalkenyl,cycloalkynyl, alkyl, alkenyl or alkynyl moiety of said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl, one or more —CH₃, —CH₂—, —CH═ and/or ≡CH isoptionally replaced by one or more —NH₂, —NH—, —O—, —S—, —N═ and/or ≡N,respectively; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, orheterocycle-alkynyl, can be unsubstituted or substituted with one ormore Z¹; and wherein a carbon atom or heteroatom of said alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl, or heterocycle-alkynyl can be oxidized to form aC═O, C═S, N═O, N═S, S═O or S(O)₂; each of R^(2a) and R^(2b) isindependently selected from hydrogen; cyano; alkyl; alkenyl; alkynyl;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; or heterocycle-alkynyl or when R^(2a) and R^(2b)are taken together to form vinyl or vinylalkyl; wherein in the alkyl,alkenyl or alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl,heterocycle-alkynyl or vinylalkyl, one or more —CH₃, —CH₂—, —CH═ and/or≡CH is optionally replaced by one or more —NH₂, —NH—, —O—, —S—, —N═and/or ≡N, respectively; and wherein said alkyl, alkenyl, alkynyl,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl, heterocycle-alkynyl, vinyl or vinylalkyl, can beunsubstituted or substituted with one or more Z¹; and wherein optionallya carbon atom or heteroatom of said alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl,heterocycle-alkynyl, or vinylalkyl can be oxidized to form a C═O, C═S,N═O, N═S, S═O or S(O)₂. R³ is independently selected from —COOH; —CN;—CONH₂; —COOZ²; —C(O)NHCN; —C(O)NHOH; —S(O)₂OH; —S(O)₂NHZ⁴;—P(O)(OH)NH₂; —P(O)(OH)O-alkyl; —P(O)(O-alkyl)₂; —P(O)OH₂;—NHC(O)NHS(O)₂-aryl; —NHC(O)NHS(O)₂-heteroaryl; —C(O)NHS(O)₂-aryl;—C(O)NHS(O)₂-heteroaryl; —S(O)₂NHS(O)₂-aryl; —S(O)₂NHS(O)₂-heteroaryl;or from the following structures:

or R²a and R³ or R^(2b) and R³ can be taken together to form a 4, 5, 6or 7-membered lactone; R⁴ is independently selected from hydrogen;halogen; cyano; hydroxyl; alkyl; alkenyl, alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl; wherein in the alkyl, alkenylor alkynyl moiety of said alkyl, alkenyl, alkynyl, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, orheterocycle-alkynyl, one or more —CH₃, —CH₂—, —CH═ and/or δCH isoptionally replaced by one or more —NH₂, —NH—, —O—, —S—, —N═ and/or ≡N,respectively; and wherein said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl, or heterocycle-alkynyl can be unsubstituted orsubstituted with one or more Z¹; and wherein optionally a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl, orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; R⁵ and R⁶ are taken together to form a 4, 5, 6, 7, or 8-memberedunsaturated cycloalkyl moiety, a 4, 5, 6, 7, or 8-membered aryl moiety,or a 4, 5, 6, 7, or 8-membered mono-unsaturated, multi-unsaturated oraromatic O, S and/or N containing heterocycle together with the carbonatoms to which they are attached; wherein said 4, 5, 6, 7, or 8-memberedunsaturated cycloalkyl moiety, 4, 5, 6, 7, or 8-membered aryl moiety, or4, 5, 6, 7, or 8-membered mono-unsaturated, multi-unsaturated oraromatic O, S and/or N containing heterocycle can be unsubstituted orsubstituted with one or more Z¹; and wherein a carbon atom or heteroatomof the 4, 5, 6, 7, or 8-membered unsaturated cycloalkyl moiety, 4, 5, 6,7, or 8-membered aryl moiety, or 4, 5, 6, 7, or 8-memberedmono-unsaturated, multi-unsaturated or aromatic O, S and/or N containingheterocycle can be oxidized to form a C═O, C═S, N═O, N═S, S═O or S(O)₂.each Z¹ is independently selected from the group consisting of hydrogen;halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl;nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³; cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl;heterocycle-alkynyl; and wherein in the alkyl, alkenyl or alkynyl moietyof said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl, one ormore —CH₃, —CH₂—, —CH═ and/or ≡CH is optionally replaced by one or more—NH₂, —NH—, —O—, —S—, —N═ and/or ≡N, respectively; and wherein saidalkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be unsubstituted or substituted with one or moreZ¹¹; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; or two Z¹ on the same carbon atom can be taken together to form a5, 6 or 7-membered spiro-cycloalkyl, spiro-cycloalkenyl,spiro-cycloalkynyl, or a saturated or unsaturated spiro-heterocycletogether with the (4, 5, 6, 7 or 8-membered unsaturated) ring they areattached to; or two Z¹ on adjacent atoms can be taken together to form a5, 6 or 7-membered cycloalkyl, cycloalkenyl, cycloalkynyl, aryl orheterocycle fused to the (4, 5, 6, 7, or 8-membered unsaturated) ringthey are attached to; each Z¹¹ is independently selected from the groupconsisting of hydrogen; halogen; —OZ¹²; —SZ¹²; —S(O)Z¹³; —S(O)₂Z¹³;—SO₂NZ¹⁴Z¹⁵; trifluoromethyl; nitro; —NZ¹⁴Z¹⁵; —NZ¹²S(O)₂Z¹³; cyano;—COOZ¹²; —C(O)NZ¹⁴Z¹⁵; —C(O)Z¹³; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkyl, arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl; each Z² and Z¹² isindependently selected from hydrogen; alkyl; alkenyl; alkynyl; aryl;heterocycle; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl or heterocycle-alkynyl; and wherein in said alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH₃, —CH₂—,—CH═ and/or ≡CH is optionally replaced by one or more —NH₂, —NH—, —O—,—S—, —N═ and/or ≡N, respectively; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; each Z³ and Z¹³ is independently selected from hydroxyl; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein in said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH₃, —CH₂—,—CH═ and/or ≡CH is optionally replaced by one or more —NH₂, —NH—, —O—,—S—, —N═ and/or ≡N, respectively; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; each Z⁴, Z⁵, Z¹⁴ and Z¹⁵ is independently selected from hydrogen;alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein in said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl, one or more —CH₃, —CH₂—,—CH═ and/or ≡CH is optionally replaced by one or more —NH₂, —NH—, —O—,—S, —N═ and/or ≡N, respectively; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; and wherein Z⁴ and Z⁵, and Z¹⁴ and Z¹⁵ respectively can be takentogether in order to form a (5-, 6-, or 7-membered) heterocycle whichcan be unsubstituted or substituted with alkyl, alkenyl, alkynyl,hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl, -OCF₃, cyano, nitro,—COOH or —NH₂; and isomers (in particular stereo-isomers or tautomers),solvates, hydrates, salts (in particular pharmaceutically acceptablesalts) or prodrugs thereof, provided that the compounds are not selectedfrom[2-(2-methoxy-5-methylphenyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2,7-dimethyl-4-(2-furanyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[4-(2-thienyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2,7-dimethyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2,7-dimethyl-4-(m-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[4-(4-chlorophenyl)-2-methyl-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[4-(4-chlorophenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[4-(p-anisyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Ethyl[2-(2-thienyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-(4-ethoxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-(4-iodophenyl)-4-phenyl-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-(4-propoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-(3,4-dipropoxyphenyl)-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-(4-pentyloxyphenyl)-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;Ethyl[4-(p-tolyl)-2-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Ethyl[4-phenyl-2-(2-thienyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;[4-(3-fluorophenyl)-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-methyl-4-phenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-(2-thienyl)-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid.
 2. The compound according to claim 1, wherein, each Z¹ isindependently selected from the group consisting of hydrogen; halogen;—OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³; —SO₂NZ⁴Z⁵; trifluoromethyl; nitro;—NZ⁴Z⁵; —NZ²S(O)₂Z³; cyano; —COOZ²; —C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; heterocycle-alkynyl; and whereinsaid alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl,optionally includes one or more heteroatoms, said heteroatoms beingselected from the atoms O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; or two Z¹ on the same carbon atom can be taken together to form aspiro-carbocycle or a saturated or unsaturated spiro-heterocycletogether with the 4, 5, 6, 7 or 8-membered unsaturated ring they areattached to; or two Z¹ on adjacent atoms can be taken together to form afused ring system together with the 4, 5, 6, 7 or 8-membered unsaturatedring they are attached to.
 3. The compound according to claim 1, whereinR³ is —COOH.
 4. The compound according to claim 1, wherein R¹ isselected from aryl or heteroaryl, wherein said aryl or heteroaryl can beunsubstituted or substituted with one or more Z¹.
 5. The compoundaccording to claim 1, wherein one of R^(2a) and R^(2b) is hydrogen, andthe other of R^(2a) and R^(2b) is selected from cyano; alkyl; alkenyl;alkynyl; arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; or heterocycle-alkynyl; wherein said alkyl,alkenyl, alkynyl, arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl; or heterocycle-alkynyloptionally includes one or more heteroatoms, said heteroatoms in thealkyl, alkenyl or alkynyl moiety being selected from the atoms O, S andN; wherein said alkyl, alkenyl, alkynyl, arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl; orheterocycle-alkynyl vinyl or vinylalkyl, can be unsubstituted orsubstituted with one or more Z¹; and wherein optionally a carbon atom orheteroatom of said alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂.
 6. The compound according to claim 1, wherein the compound has astructure according to formula (A-1)

wherein each of R¹, R^(2a), R^(2b), R³, and R⁴ is as in claims 1 to 5and each dotted line represents an optional double bond wherebymaximally two non-adjacent dotted lines can form a double bond; W, X, Y,and Z are independently selected from CR′, CR′R″, N, NR′″, O and Sdepending on whether they are adjacent to a double or a single bond,wherein R′, R″ and R′″ are independently selected from the groupconsisting of hydrogen; halogen; —OZ²; —SZ²; —S(O)Z³; —S(O)₂Z³;—SO₂NZ⁴Z⁵; trifluoromethyl; nitro; —NZ⁴Z⁵; —NZ²S(O)₂Z³; cyano; —COOZ²;—C(O)NZ⁴Z⁵; —C(O)Z³; alkyl; alkenyl; alkynyl; aryl; heterocycle;arylalkyl; arylalkenyl; arylalkynyl; heterocycle-alkyl;heterocycle-alkenyl; heterocycle-alkynyl; and wherein said alkyl,alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl,optionally includes one or more heteroatoms, said heteroatoms beingselected from the atoms O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; R′ or R″ on the same carbon atom can be taken together to form a5, 6 or 7-membered spiro-cycloalkyl, spiro-cycloalkenyl,spiro-cycloalkynyl or a saturated or unsaturated spiro-heterocycletogether with the 5, 6 or 7-membered unsaturated ring they are attachedto; or an R′ and another R′, R″ or R′″ on adjacent atoms can be takentogether to form a 5, 6 or 7-membered cycloalkyl, cycloalkenyl,cycloalkynyl, aryl or heterocycle fused to the 5, 6 or 7-memberedunsaturated ring they are attached to; each Z² is independently selectedfrom hydrogen; alkyl; alkenyl; alkynyl; aryl; heterocycle; arylalkyl;arylalkenyl; arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein said alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally include one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; each Z³ is independently selected from hydroxyl; alkyl; alkenyl;alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl; arylalkynyl;heterocycle-alkyl; heterocycle-alkenyl or heterocycle-alkynyl; andwherein said alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl,arylalkenyl, arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl optionally includes one or more heteroatoms, saidheteroatom selected from O, S and N; and wherein said alkyl, alkenyl,alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl, arylalkynyl,heterocycle-alkyl, heterocycle-alkenyl or heterocycle-alkynyl can beunsubstituted or substituted with alkyl, alkenyl, alkynyl, hydroxyl,halogen, —SH, trifluoromethyl, —O-alkyl, —OCF₃, cyano, nitro, —COOH orNH₂; and wherein optionally a carbon atom or heteroatom of said alkyl,alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be oxidized to form a C═O, C═S, N═O, N═S, S═O orS(O)₂; each Z⁴ and Z⁵ is independently selected from hydrogen; alkyl;alkenyl; alkynyl; aryl; heterocycle; arylalkyl; arylalkenyl;arylalkynyl; heterocycle-alkyl; heterocycle-alkenyl orheterocycle-alkynyl; and wherein said alkyl, alkenyl, alkynyl, aryl,heterocycle, arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl optionally includes one ormore heteroatoms, said heteroatom selected from O, S and N; and whereinsaid alkyl, alkenyl, alkynyl, aryl, heterocycle, arylalkyl, arylalkenyl,arylalkynyl, heterocycle-alkyl, heterocycle-alkenyl orheterocycle-alkynyl can be unsubstituted or substituted with alkyl,alkenyl, alkynyl, hydroxyl, halogen, —SH, trifluoromethyl, —O-alkyl,—OCF₃, cyano, nitro, —COOH or NH₂; and wherein optionally a carbon atomor heteroatom of said alkyl, alkenyl, alkynyl, aryl, heterocycle,arylalkyl, arylalkenyl, arylalkynyl, heterocycle-alkyl,heterocycle-alkenyl or heterocycle-alkynyl can be oxidized to form aC═O, C═S, N═O, N═S, S═O or S(O)₂; and wherein Z⁴ and Z⁵ can be takentogether in order to form a (5-, 6-, or 7-membered) heterocycle whichcan be unsubstituted or substituted with alkyl, alkenyl, alkynyl,hydroxyl, halogen, —SH, trifluoromethyl, ——O-alkyl, —OCF₃, cyano, nitro,—COOH or —NH₂; and n is selected from 0; 1; or
 2. 7. The compoundaccording to claim 1, wherein the compound has a structure according toformula (B),

wherein, each dotted line represent an optional double bond wherebymaximally two non-adjacent dotted lines can form a double bond; each ofR¹, R^(2a), R^(2b), R³, R⁴ and Z¹ are as in claims 1 to 4; n is selectedfrom 0; 1; or 2; and m is selected from 0; 1; 2; 3; 4; 5 or
 6. 8. Thecompounds according to claim 1, selected from the list of:Methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;Methyl[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]acetate;Methyl[7-methyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;Methyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]acetate;Methyl[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(2-methyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Ethyl[7-benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;Ethyl2-[2,7-dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;Ethyl2-[2-methyl-4-(p-tolyl)-spiro[[1,3]dioxolane-2,7]-5,6,7,8-tetrahydro-9-thia-1-aza-7-oxo-fluoren-3-yl]pentanoate;Ethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxymethylether-butanoate;Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]-4-O-methoxy-butanoate;Methyl2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acrylate;Methyl2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylacetate;Methyl2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoate;Methyl2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-benzyloxypropanoate;Methyl2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoate;Methyl 2-[2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate; Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoate;Methyl2-[2-methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoate;Methyl2-[2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[l]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yl-oate;Methyl2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;Methyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoate;Ethyl2-[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoate;2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]aceticacid;[2-Methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;(2S)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;(2R)-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-trifluoromethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid; 2-[2-Methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;3-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]dihydrofuran-2(3H)-one;2-[2-methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-4-O-methoxy-butanoicacid;2-[2-Methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2-cyclopentylaceticacid;2-[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-acrylicacid;2-[2-Methyl-4-(p-tolyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-methoxypropanoicacid;2-[2-phenyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-methyl-7-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(2-furyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(p-anisyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,8-dihydro-6H-7-oxa-9-thia-1-aza-fluoren-3-yl]pentanoicacid;2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoicacid; 2-[2-Methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoic acid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-methylpentanoicacid;2-[2-Methyl-4-(2-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(3-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(m-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(m-anisyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(3,4-dimethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(benzo[d][1,3]dioxol-5-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-6,6,6-trifluorohexanoicacid;2-[2-Methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-ethylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(4-trifluoromethoxyphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(2-methyl-1-propyl-1H-indol-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(2-fluorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylbutanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-methylpentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-5,5,5-trifluoropentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-pent-4-yl-oicacid;2-[2-methyl-4-(2-methoxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-Methyl-4-(2-hydroxy-4-methylphenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoateammonium salt;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4,4-dimethylpentanoicacid;2-[7-Benzyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid;2-[2,7-Dimethyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoicacid;2-[2-Methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-3-cyclopropylpropanoicacid;N-cyano-2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide;2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanamide;Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;Methyl2-[2-methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate;2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyaceticacid; Methyl2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-Methyl-4-(pyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid2-[2-Methyl-4-p-tolyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanenitrile;2-Methyl-4-(p-tolyl)-3-[1-(1H-tetrazol-5-yl)butyl]-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine;Methyl 2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(1-methyl-1H-pyrazol-4-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;3-(1-[2-methyl-6-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]butyl)-1,2,4-oxadiazol-5(4H)-one;Ethyl[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Ethyl2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;2-[2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;5-[1-(2-ethyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butyl]thiazolidine-2,4-dione;Ethyl(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)carboxylate;Methyl2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(6-methylpyridin-3-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid; Methyl2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(benzo[d]thiazol-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid; Methyl2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid; Methyl2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(8-fluoro-5-methylchroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid; Methyl2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(5-chlorochroman-6-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]methylphosphonate;Dimethyl[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]butylphosphonate;1-(2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)butylphosphonicacid; Methyl2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(phenylthio)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;Ethyl[7-acetyl-2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoate;[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,7-diaza-fluoren-3-yl]pentanoateammonium salt;[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,6-diaza-fluoren-3-yl]pentanoateammonium salt;[2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro-9-thia-1,8-diaza-fluoren-3-yl]pentanoateammonium salt; Methyl2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyacetate;2-[2-methyl-4-(phenyloxy)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid;2-[2-methyl-4-(phenylamino)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-tert-butoxyaceticacid.[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]aceticacid;[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate;Methyl2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate;2-[2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid;2-[2-hydroxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoicacid. 9-16. (canceled)
 17. A method for the preparation of the compoundsaccording to claim 1 comprising the steps of: reacting abeta-ketonitrile of formula R¹—C(O)CH₂CN with a compound of formulaR⁶C(O)CH₂R⁵ in the presence of sulfur and a strong base in a polarprotic solvent or in a polar aprotic solvent at a temperature between60° C. to 100° C.; reacting the obtained 2-aminothiophene reactionproduct of the previous step with a compound of formula R⁴C(O)CH₂CH₂R³in the presence of trimethyl chlorosilane in a polar aprotic solvent ata temperature between 50° C. and 200° C.; optionally, reacting thecompound obtained in the previous step with a compound having astructure of the formula R^(2a)-leaving group and/or R^(2b)-leavinggroup through a nucleophilic substitution.
 18. A method for thepreparation of the compounds according to claim 1 comprising the stepsof: reacting a cyanoacetate derivative of formula ROC(O)CH₂CN with acompound of formula R⁶C(O)CH₂R⁵ in the presence of sulfur and a strongbase in a polar protic solvent or in a polar aprotic solvent at atemperature between 20° C. to 100° C.; reacting the previously obtained2-amino-4,5-disubstituted-thiophene-3-carboxylate derivative with acompound of formula R⁴C(═CHCOOZ²)OZ² in an apolar aprotic solvent at atemperature between 80° C. and 140° C. to obtain an enamine intermediatewhich undergoes an intramolecular ring cyclization in the presence of astrong base in a polar protic solvent to provide a5,6-substituted-4-hydroxythieno[2,3-b]pyridine-5-carboxylate derivative;the 4-hydroxyl function can then be converted to an halogen withstandard procedures know to the skilled in the art; the ester functioncan then be reduced to a primary alcohol which is immediately oxidizedinto an aldehyde following standard procedures known to the skilled inthe art; the5,6-substituted-4-halogenothieno[2,3-b]pyridine-5-carbaldehydederivative is then converted into a2-(5,6-substituted-4-halogenothieno[2,3-b]pyridin-5-yl)-2-hydroxyacetatederivative using an addition of trimethylsilylcyanide in the presence ofzinc iodide followed by hydrolysis in acidic conditions; the R^(2a) andor R^(2b) residues can then be introduced following procedures known tothe skilled in the art; substituting the 4-halogen atom from thepreviously obtained compound in a specific manner (amination,alkylation, arylation) with suitable chemical reagents to obtain thedesired compounds; hydrolyzing the ester compounds obtained in theprevious step to obtain the desired free carboxylic acid derivatives.19. A pharmaceutical composition comprising the compounds according toclaim 1 as an active ingredient in admixture with at least apharmaceutically acceptable carrier.
 20. The pharmaceutical compositionaccording to claim 19, having antiviral activity.
 21. The pharmaceuticalcomposition according to claim 20, having anti-HIV activity.
 22. Thepharmaceutical composition according to claim 19, further comprising acompound with antiviral activity selected from reverse transcriptaseinhibitors, protease inhibitors, integrase inhibitors, entry inhibitorsand compounds with other mechanisms of action.
 23. A method of treatmentor prevention of a viral infection in an animal or mammal, comprisingadministering to the animal or mammal in need of such treatment atherapeutically effective amount of a compound according to claim
 1. 24.(canceled)